IndraLab
Statements
AKT activates MTOR. 1000 / 1575
1
|
44
6
1106
366
reach
"The activation of the PI3K and AKT signaling pathway stimulates mTOR signaling cascades, modulating two master molecules associated with the initiation of mRNA translation, namely, 70-kDa ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1)."
sparser
"More specifically, in nutrient rich conditions or stimulation by growth factors, Akt activates mTOR Complex 1 (mTORC1), suppressing autophagy by phosphorylation-dependent inhibition of Unc-51 like-autophagy activating kinase 1/2 (ULK1/2) and the Vacuolar protein sorting 34 (Vps34) complex [ xref ]."
reach
"Since mTOR is activated by Akt, although it is not clear if this is a direct or indirect activation [reviewed in [XREF_BIBR]], we decided to monitor if Akt was activated by IR by studying its phosphorylation state, which was reported to be an early response to IR [XREF_BIBR, XREF_BIBR]."
sparser
"The mechanistic target of rapamycin (mTOR) is also activated by AKT and increases the level of HIF-1α, which can directly increase the expression of vascular endothelial growth factor (VEGF) or bind to HIF-1β in hypoxia conditions and transfer to the nucleus to promote the expressions of erythropoietin (EPO) and VEGF."
reach
"Furthermore, radiation exposure has been intimately linked to increased reactive oxygen species (ROS) production and persistent oxidative stress in cells, and oxidative stress has been reported to activate the pro growth PI3K and Akt pathway, which in turn is known to activate mTOR [XREF_BIBR, XREF_BIBR]."
reach
"XREF_BIBR, XREF_BIBR Nevertheless, considerable evidence exists to show that insulin can enhance the activation of mTOR via stimulation of 4EBP1 binding to dimeric mTOR complex 1, XREF_BIBR and mediated by the Akt and PKB substrate PRAS40 (proline rich Akt and PKB substrate 40 kDa)."
sparser
"Several downstream targets including the serine/threonine kinase Akt that activates mTOR are activated by PI3K. Furthermore, activation of this pathway is known to decrease sensitivity to chemotherapeutics as well as to irradiation (IR)[ xref , xref ], resulting in a limited treatment outcome."
reach
"XREF_BIBR In addition, this same group showed that pharmacological activation of TGR5 in bone marrow derived macrophages, reduced lipopolysaccharide induced chemokine production by a mechanism that required AKT dependent activation of mTOR complex 1 (mTORC1), which stimulated production of the dominant negative CCAAT and enhancer binding protein isoform, liver inhibitory protein."
sparser
"The PI3K-AKT-mTOR axis could be considered to be a single pathway [ xref ] in which AKT activates mTOR to control cell proliferation and growth in response to environmental stimuli by phosphorylating and inactivating the mTOR suppressors tuberous sclerosis protein 1 (TSC1) and TSC2 [ xref , xref ]."
reach
"In canonical growth factor signaling, mTOR is activated by PI3K/Akt, through IGF-1 and insulin signaling, but a considerable body of evidence suggests that mTORC1 is also likely activated by a growth factor-independent movement of proteins to and from the lysosome, via resistance exercise-induced phosphorylation of TSC2 [77]."
reach
"Because the binding of insulin to its receptors activates the PI3K and AKT pathway, which is known to stimulate mTOR activity, Kalaany and Sabatini 's observations that tumor cells bearing constitutively activated PI3K mutations are proliferative in vitro in the absence of insulin or IGF-1 and form DR resistant tumors in vivo [XREF_BIBR] clearly suggest that cancer cell-autonomous alterations (e.g., activating mutations of PI3K) may ultimately determine the response of cancer cells to CR, DR, or CRMs."
sparser
"Previous studies have revealed that Akt (protein kinase B, also known as PKB), an important upstream signaling protein of mTOR, activates mTOR, which in turn promotes protein synthesis through the phosphorylation and activation of ribosomal protein S6 kinase (S6K1), and the phosphorylation and inactivation of the mRNA translation repressor, known as eukaryotic initiation factor 4E-binding protein (4E-BP1) [ xref , xref ]."
eidos
"Activation of mTOR by AKT decreases autophagy , and decreased autophagy induces stem cells to differentiate into osteoblasts as well as promotes the calcification of smooth muscle cells.17 , 18 We observed that the mTOR inhibitor rapamycin reduced ALPL gene expression and TNAP activity and prevented calcification of CD73-deficient cells ( Figure 2A-C ) ."
reach
"have reported the existence of a protective pathway in cardiomyocytes which involves p38 and Akt mediated mTOR activation in an ischemia and reperfusion model of C75 and B16 mice, while other researchers have postulated an increased phosphorylation of MAPK (e.g. p38) and mTOR in branchial arch muscles from 8- to 26-months-old F344 rats."
sparser
"Direct activation of mTOR by AKT was assessed using a phospho-specific antibody directed toward S2448 ( xref ), a phospho-site that correlates with increased mTORC1 activity and up-regulated protein synthesis ( xref ). xref illustrates that mTOR is phosphorylated within 15 min of BDNF stimulation, and this S2448 phosphorylation is blocked by treatment with STO-609."
reach
"Physiological hypertrophy is initiated by finite signals, which include growth hormones (such as thyroid hormone, insulin, insulin like growth factor 1 and vascular endothelial growth factor) and mechanical forces that converge on a limited number of intracellular signalling pathways (such as PI3K, AKT, AMP activated protein kinase and mTOR) to affect gene transcription, protein translation and metabolism."
sparser
"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."
reach
"Activation of the PI3K/AKT pathway also increases the activity of the serine/threonine kinase mechanistic target of rapamycin complex 1 (mTORC1) through the phosphorylation and inhibition of the mTORC1 inhibitor TSC; mTORC1 then serves as a major stimu- lant of anabolic metabolism (Liu and Sabatini, 2020; Manning and Toker, 2017; Mossmann et al., 2018)."
sparser
"Insulin induces phosphorylation of Akt, which then activates mammalian target of rapamycin complex 1 (mTORC1) via inhibition of TSC1/2, leading to activation of SREBP1c, an adipogenic transcription factor which regulates fatty acid synthase, lipoprotein lipase and PPARγ expression [ xref , xref , xref , xref , xref ]."
reach
"Subsequently, activated PI3K or Akt may positively regulate mTOR, leading to increased phosphorylation of ribosomal p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), the two best characterized downstream effector molecules of mTOR [XREF_BIBR - XREF_BIBR]."
reach
"Interestingly, both the mTORC1 inhibitor rapamycin (100 nmol/L) and the AMPK inducer AICAR decreased the BCAA‐induced activation of Akt and mTORC1 (Figure 1D,E) suggesting that in response to BCAA, AMPK is likely activated to counteract the Akt/mTOR pathways and that there is a reciprocal relationship between mTORC1 and Akt."
reach
"Akt/protein kinase B (PKB) lies upstream of mTOR, so activated Akt may positively regulate mTOR, leading to increased phosphorylation of ribosomal p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two best characterized downstream effector molecules of mTOR [23]."
sparser
"The regulation of mTOR by the LKB1/AMPK signal functionally and mechanistically parallels that of the phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) signal where AKT activates mTOR via TSC2. xref Similar to LKB1, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), the negative regulator of PI3K/AKT, functions as a tumor suppressor in a plethora of cancer types."
reach
"In addition, we hypothesize that galangin and pinocembrin may have a synergistic effect via Akt and mTOR signaling pathway, while galangin and pinocembrin upregulate the phosphorylation of IR, Akt, and GSK3beta, downregulate the phosphorylation of IRS, and activate Akt and mTOR pathway."
reach
"AKT, protein kinase B alpha; ER, endoplasmic reticulum; IKKβ, I-kappa-B kinase beta; IKKɛ, I-kappa-B kinase epsilon; IRS1/2, insulin receptor substrate 1; ISRE, interferon-stimulated response element; MAVS, mitochondrial antiviral signaling protein; mTOR, mechanistic target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI-3K, phosphoinositide-3-kinase; STAT1/2/3/4/5/6, signal transducer and activator of transcription 1/2/2/4/5/6; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1.Fig."
reach
"These results suggested that cyst fluid TNFalpha might act through PI3K-Akt mediated activation of mTOR to increase the levels of Id2 to regulate cyst lining epithelial cell proliferation during cyst development, which might be one of the reasons that rapamycin could inhibit cyst lining epithelial cell proliferation in Pkd1 knockout mouse models [XREF_BIBR]."
reach
"Expression and/or activation of the mitogen activated protein kinase MAPK (RAS/RAF/ERKs) and phosphatidylinositol 3-kinases (PI3Ks)/protein kinase B (PKB-AKT)/mammalian target of rapamycin kinase (mTOR) pathways are abnormally high in many HCC cells, which render the latter resistant to apoptotic stimuli XREF_BIBR - XREF_BIBR."
sparser
"Various members of this PKC family have been implicated in progression of cell cycle, apoptosis and differentiation. xref Protein kinase A family of proteins is activated in response to G coupled protein receptors xref while PRKCD plays a key role in autophagy suppression which is achieved by the process of phosphorylation of AKT which further activates mTOR, specific for fibrolamellar carcinoma. xref In current study, activity of c-SRC decreases with progressive liver fibrogenesis and hepatic stellate cell (HSC) activation."
reach
"The activation of regulators such as growth factors receptor recruits PI3K to the cell membrane and phosphorylates AKT which later induces mTOR activation leading to the activation of its downstream effectors (4EBP1 and P70S6) and eventually induces RNA translation, protein synthesis, cell survival, and so on [18] ."
reach
"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."
reach
"XREF_BIBR - XREF_BIBR Once activated, AKT can target downstream modulators of apoptosis such as GSK3beta, IRS-1 (insulin receptor substrate-1), PDE-3B (phosphodiesterase-3B), BAD, caspase-9, Forkhead proteins, NF-kappaB, mTOR, nitric oxide synthase (NOS), Raf protein kinase, and BRCA1."
reach
"Phosphoinositide 3-kinase (PI3K), pyruvate dehydrogenase kinase (PDK), and protein kinase B (PKB; Akt) activation induced by growth factors (GFs) activate the mammalian target of the rapamycin (mechanistic target of rapamycin kinase; mTOR) pathway, which results in elevated HIF-1α transcriptional activity [6]."
| PMC
sparser
"Akt indirectly activates mTOR, a complicated checkpoint of cellular growth influenced by growth factor signaling, adenosine monophosphate levels, and nutrient and O 2 availability. xref mTOR refers to 2 distinct multimolecular complexes, mTOR complex 1 (mTORC1) and complex 2 (mTORC2)."
sparser
"As a downstream effector of PI3K, Akt is involved in regulation of various signaling pathways involved in cell metabolism, proliferation, survival, growth, and angiogenesis. xref Akt can activate mTOR at Ser2448, which plays a key role in cell growth, autophagic cell death, and homeostasis. xref PTEN is a negative regulator of PI3K and inhibits Akt/mTOR and MAPK signaling, leading to inhibition of cell growth and cell death. xref The results show that danusertib inhibited activation of Akt at Ser473 without a significant change in expression of total Akt in either cell line ( xref )."
sparser
"Subsequently pAkt activates mTOR to enhance HIF-1α transactivation activity, HIF-1α/HIF-1β bind to the HRE of VEGF promoter region to induce VEGF production, then 33-kDa ANXA3 promoted angiogenesis of HepG2 cells through activating PI3K/Akt via increasing HIF-1α expression; (3) Furthermore, pAkt decreases Bax and increases Bcl-2 expressions, Bax upregulation and Bcl-2 downregulation promoted cytochrome c release from mitochondria into the cytoplasm, then binds to Apaf-1 and forms apoptosome to recruits and activates pro-caspase 9, following by pro-caspase 3 cleavage and activation, cleaved-caspase 9 and cleaved-caspase 3 blocked DNA damage repair to induce apoptosis, then 33-kDa ANXA3 inhibited HepG2 cells apoptosis and chemoresistance via activating caspase 9 and caspase 3."
reach
"The activated PI3K and Akt may further activate its downstream molecule mTOR through the TSC1/2 complex, and the activated mTOR can activate its two downstream molecules subsequently, which are the translation inhibitory molecule eIF-4E binding protein 1 (4E-BP1) and ribosomal protein p70S6K."
reach
"While this finding was not unexpected, as plasma amino acid levels were dramatically decreased in these mice and branched-chain amino acids are known stimulators of insulin release XREF_BIBR, our finding that the phosphorylation of Akt was unchanged in response to dietary protein intake indicates that insulin and Akt does not mediate the observed changes in mTOR activity."
reach
"Akt directly and indirectly activates mammalian target of rapamycin (mTOR) signaling by enhancing its downstream molecules, including eukaryotic initiation factor 4E-binding protein (4E-BP1) and ribosomal protein S6 kinase (S6K), and promoting cell differentiation, growth, and survival (Martelli et al., 2010; Sabbah et al., 2011)."
reach
"It has been demonstrated that PI3K/AKT can activate its downstream factors mTOR and Nrf2 (Kim et al., 2013), which are involved in axon branching, autophagy, alleviating oxidative damage, and down-regulating tau protein phosphorylation as well as apoptosis of neurons via inhibiting caspase 3 and glycogen synthase kinase (GSK) -3β (Chami et al., 2016)."
reach
"The lower mTOR activation in the 19R group than in the 19S group, even on the isocaloric and isoprotein diets, may be the result of insulin deficiency that decreased Akt (an activator of mTOR) [XREF_BIBR] phosphorylation and activated PTEN in the 19R group compared to the 19S group."
reach
"Autophagy is regulated by several cellular signaling pathways, class I phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)-mammalian target of rapamycin complex 1 (mTORC1), and other mTOR independent pathways, for instance, cyclical Ca 2+ -calpain-Galphas and cAMP-Epac-PLC-epsilon-IP3 and the basic helix-loop-helix leucine zipper transcription factor EB (TFEB)-mediated pathway [XREF_BIBR] (XREF_FIG)."
sparser
"Akt can directly phosphorylate and activate mTOR, as well as indirectly activating it by phosphorylating and inactivate tuberous sclerosis complex 2 (TSC2), also called tuberin, which normally inhibits mTOR through the GTP binding protein Ras homolog enriched in brain (Rheb) [ xref ]."
reach
"In summary, full understanding of the molecular mechanisms, signaling pathways, and the secondary causes of muscle and/or fat wasting are essential for successful CC management.Table 1: List of therapeutic agents and factors available for the management of cancer cachexia.Figure 1: The common assessment for the clinical management of cancer cachexia.Figure 2: Molecular mechanisms regulated by IGF-1 and MSTN: Active Akt produces the mTOR signal, which leads to protein synthesis and inhibits (phosphorylates) FoxO."
sparser
"AKT activates MTOR by a cascade of phosphorylations, and MTOR inhibits autophagy through the inhibitory phosphorylation of ULK1 (unc-51 like autophagy activating kinase 1) and ATG13, proteins required for autophagy induction. xref GSK3 has recently been shown to be part of this regulatory cascade."
reach
"We then analyzed the activities of Akt kinase and AMPK kinase, two major kinases controlling mTOR activity : The Akt kinase mediates the activation of mTOR in response to growth factors, and the AMPK kinase is involved in mTOR activity inhibition in response to nutritional, genotoxic and metabolic stress signals [XREF_BIBR, XREF_BIBR]."
eidos
"Suppression of mTOR signaling by the expression of a dominant negative mutant of the Akt kinase cause an increase in Bcl-2 phosphorylation in HEK23 human embryonic kidney cells [ 45 ] , suggesting that Akt inactivation may inhibit mTOR expression and upregulate Bcl-2 phosphorylation , thereby preventing cell apoptosis ."
reach
"Phosphatidylinositol 3 kinase (PI3K) can be activated in response to growth factors and several hematopoietic cytokines leading to the activation of downstream kinases such as the serine/threonine kinase Akt (also known as protein kinase B or PKB) that, in turn, can activate the mTOR (mammalian target of rapamycin) complex."
reach
"Mammalian target of rapamycin (mTOR) signaling, downstream of PI3K-AKT signaling activation, could be activated by phosphorylation of AKT to regulate autophagy process via mTOR-Atg1-Atg13 or mTOR-ULK1-Atg13 signal transduction under pressure stimulation or oxidative stress stimulation [33]."
reach
"However, AKT mediated mTOR activation can occur through a variety of mechanisms, including direct mTOR activation [XREF_BIBR], phosphorylation of the proline rich in AKT substrate of 40 kDa (PRAS40) [XREF_BIBR], or through inactivation of the tuberous sclerosis complex (TSC) [XREF_BIBR]."
sparser
"Activated AKT (or p-AKT) could further activate mTOR by phosphorylation, which could regulate cell stress response and cell cycle. xref As PTEN mutations are seen early in endometrioid ovarian carcinoma and endometrioid ovarian cancer is thought to arise from EMs, it has been proposed that somatic genetic alterations in the PTEN gene may be an early event in MTOE. xref The ovarian endometrioid adenocarcinoma with an activated PI3K–AKT–mTOR signaling pathway is more likely to be of a low grade instead of a high grade. xref In our present research, PTEN expression was progressively reduced in the order of EMs, atypical EMs, and malignant EMs."
reach
"Welker et al previously indicated that, through the PI3K/AKT/mTOR signaling pathway, activated AKT activates mTOR and regulates two downstream factors, consisting of eukaryotic initiation factor 4E binding protein 1 and ribosomal S6 protein kinase 1, in addition to controlling the translation of proteins for cell proliferation and transformation."
sparser
"Akt activates mTOR through (i) phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which inactivates the mTOR-activating GTP-binding protein Rheb, and/or (ii) phosphorylation of PRAS40 a member of mTORC1, one of the two functional complexes of mTOR, which includes mLST8/Gbl and the scaffold protein Raptor ( xref )."
sparser
"Previous studies have demonstrated that RAS suppressed cMYC-induced apoptosis via activating PI3K/AKT pathway. xref Activated AKT in turn phosphorylates and activates mammalian target of rapamycin (mTOR), an essential component of mTORC1 that promotes tumor cell proliferation and survival. xref In cMYC/KRAS12V-transduced plasmacytoma cells, genes in mTOR target gene set xref were significantly upregulated ( xref and xref )."
reach
"As protein synthesis in skeletal muscle cells is regulated by Akt and mTOR [XREF_BIBR, XREF_BIBR], we analyzed levels of Akt and p70s6k (a downstream target of mTOR) in control, empty vector, and ICAM-1+ cells through 6 d of differentiation, as well as in ICAM-1+ cells treated with ICAM-1 peptide at 5 d of differentiation."
reach
"IL-6-induced AKT phosphorylation activates mTOR that consequently activates its downstream targets p70S6 kinase (p70S6K), 40S ribosomal protein S6 (S6RP) and the eukaryotic initiation factor 4E binding protein-1 (4EBP1), that control mRNA translation and protein synthesis [XREF_BIBR]."
sparser
"This is achieved through Akt-dependent phosphorylation and inhibition of p21 (Thr 145 ) and downregulation of p27, which relieves the G 1 checkpoint xref – xref and Chk1 inhibitory phosphorylation (Ser 280 ), inhibiting G 2 /M cell cycle arrest. xref Akt activates mTOR through direct phosphorylation at Ser 2448 , resulting in the activation of mRNA translational machinery. xref Akt also stabilizes the caspase-3 inhibitor X-linked inhibitor of apoptosis protein (XIAP) by phosphorylating Ser 87 , preventing XIAP auto-ubiquitination and subsequent proteasomal degradation. xref Akt regulates p53 protein stability and activation through phosphorylation of MDM2 on Ser 166 and Ser 186 , facilitating its nuclear translocation and thereby enhancing p53 ubiquitination and proteasomal degradation. xref , xref "
reach
"Conversely, AKT may be activating alternative pathways instead of mTOR such as activation of IkappaB kinase, a positive regulator of NF-kappaB that transcribes anti-apoptotic genes [XREF_BIBR, XREF_BIBR] or possibly mTOR is activated by AKT independent mechanisms in NPE and PSCC such as via the RAS/MEK/ERK pathway, nutrient starvation and hypoxia, among others [XREF_BIBR]."
reach
"Current models suggest that Akt positively regulates mTOR and p70S6K action by acting on mTOR-inhibitory molecules PRAS40 and TSC2, and previous work from our laboratory has established that PI3K p110alpha is the primary PI3K catalytic isoform involved in IGF-I-stimulated Akt activation in C2C12 cells (Matheny and Adamo, manuscript in press)."
sparser
"With heightened levels of insulin there is also increased PI3K production of phosphatidylinositol (3,4,5)-triphosphate (PIP3), activation of Akt (AKR mouse thymoma) kinase and increased nuclear SREBP-1 levels via Akt activation of the mammalian target of rapamycin (mTORC1) signaling complex ( xref ) [ xref ]."
reach
"Sensitization to INCB in myr-AKT-expressing cells could be fully restored with an allosteric AKT inhibitor, MK-2206 (XREF_FIG), but not with the dual phosphoinostitide 3- kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor BEZ-235 (XREF_SUPPLEMENTARY), suggesting that resistance in these cells does not depend on AKT mediated mTOR activation."
sparser
"PIP3 subsequently binds to phosphoinositide-dependent kinase 1 (PDK1), thus phosphorylating and activating the serine/threonine kinase AKT. xref , xref PTEN (phosphatase and tensin homolog), a tumor suppressor, is a phosphatase that dephosphorylates PIP3 into inactive PIP2, thereby dampening AKT and PDK1. xref , xref Activated AKT can phosphorylate and activate mTOR or indirectly promote mTOR activity by phosphorylation and inactivation of tuberous sclerosis complex 1/2, a mTOR inhibitor."
reach
"Since the oncogenic mutations in PIK3CA induce downstream signaling through the phosphorylation of AKT and subsequent activation of mTOR complex 1 (mTORC1), inhibition of PI3K, AKT, and/or mTORC1 may be an effective therapeutic strategy to treat the tumors with an oncogenic PIK3CA mutation."
sparser
"With heightened levels of insulin there is also increased PI3K production of phosphatidylinositol (3,4,5)-triphosphate (PIP3), activation of Akt (AKR mouse thymoma) kinase and increased nuclear SREBP-1 levels via Akt activation of the mammalian target of rapamycin (mTORC1) signaling complex (Figure 3) [88]."
reach
"Note: AKT, protein kinase B; COX-1, cyclooxygenase-1; cPLA2, cytoplasmic phospholipase A2; EIF2α, eukaryotic initiation factor 2 alpha; ER, endoplasmic reticulum; HK-2 cells, human kidney 2 cells; MAPK, mitogen-activated protein kinase; mitoROS, mitochondrial reactive oxygen species; mTOR, mitogen-activated protein kinase; PS-MPs, polystyrene microplastics; ROS, reactive oxygen species."
reach
"Akt activates mTOR through (i) phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which inactivates the mTOR activating GTP binding protein Rheb, and/or (ii) phosphorylation of PRAS40 a member of mTORC1, one of the two functional complexes of mTOR, which includes mLST8 and Gbl and the scaffold protein Raptor."
sparser
"Akt takes a part in the regulation of various signaling downstream pathways, including cell proliferation, growth, survival, angiogenesis, and chemoresistance. xref As a downstream effector of PI3K, Akt can activate mTOR, while mTORC2 phosphorylates Akt at Ser473 and stimulates Akt phosphorylation at Thr308 by 3-phosphoinositide-dependent protein kinase 1, leading to full Akt activation. xref mTOR plays a key role in cell growth, autophagic cell death, and homeostasis. xref mTOR is phosphorylated at Ser2448 via the PI3K/Akt signaling pathway and autophosphorylated at Ser2481. xref mTOR inhibition promotes dissociation of mTOR from the complex of Atg13 with Unc-51 like autophagy activating kinase 1 (ULK1) and ULK2."
reach
"PKB and Akt activity has been linked to increased mTOR activation through several mechanisms, including direct phosphorylation of mTOR by PKB and Akt [XREF_BIBR, XREF_BIBR], PKB and Akt mediated phosphorylation of TSC2, and inhibition of AMP kinase, which prevents the phosphorylation and inhibition of TSC2 [XREF_BIBR]."
reach
"Importantly, the mentioned anti-proliferative and pro apoptotic effects of adiponectin were seen in mostly ERalpha negative BC, while divergent effects of adiponectin were reported in ERalpha positive BC such as : (i) activation of both MAPK and Akt stimulating mTOR and p70S6K cascade, (ii) activation of ERalpha followed by recruitment of LKB1 as a receptor coactivator overall compromising AMPK and in consequence switching cancer cell energy balance vs. lipogenic aggressive phenotype, and (iii) upregulation of cyclin D1 promoting tumor growth [XREF_BIBR]."
| PMC
sparser
"Studies using pressure overloaded mice and guinea pigs reported that P70 S6 ribosomal kinase (S6K) phosphorylation is clearly correlated with cardiac hypertrophy xref , xref , and that cardiac-specific Akt overexpression increases activation of mTOR and results in cardiac hypertrophy xref , xref , xref ."
sparser
"Intrathecal administration of mTOR inhibitors was shown to significantly block the development of inflammatory and neuropathic pain. xref , xref , xref , xref Given that mTOR is important for control of protein translation and that Akt can activate mTOR in central neurons, xref , xref it is possible that mTOR participates in Akt-dependent induction of Nav1.7 and Nav1.8 expression in DRG neurons after inflammation."
reach
"The benzimidazole anthelmintics usually decreased signaling proteins related to cell proliferation and survival, such as phosphorylated (p) HER2/3, PI3K and protein kinase B (AKT), rapidly accelerated fibrosarcoma (a family of three serine/threonine specific protein kinases) (RAF)/MEK/ERK, mTOR, and Ki-67."
reach
"PKB and Akt activity has been linked to increased mTOR activation through several mechanisms, including direct phosphorylation of mTOR by PKB and Akt [XREF_BIBR, XREF_BIBR], PKB and Akt mediated phosphorylation of TSC2, and inhibition of AMP kinase, which prevents the phosphorylation and inhibition of TSC2 [XREF_BIBR]."
"It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). 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 tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor."
reach
"Taken together, these results indicate that there could be an unknown pathway through which AKT activates S6 and eIF4E independent of mTOR function or that mTOR may be influenced by additional signaling pathways in response to genetic changes or metabolic changes independently of AKT in NSCLC."
sparser
"In normal cells, PI3K activation is tightly controlled by dephosphorylation of PIP3 by the phosphatase PTEN, a potent tumor suppressor. xref Together, mutations in PI3K signaling constitute one of the most common mutations in human tumors. xref Enhanced PI3K/Akt signaling selectively gives tumors an advantage through several pathways, including (1) increased surface expression of nutrient transporters resulting in increased uptake of glucose, (2) Akt-dependent stimulation of hexokinase and phosphofructokinase to drive glycolysis, (3) enhanced transcription of genes involved in glycolysis, and (4) enhanced protein translation through Akt-dependent mTOR activation. xref "
reach
"Patient selection based on molecular events known to be associated with mTOR activation such as the overexpression of PI3K and Akt and the growth factor receptors human epidermal growth factor receptor 2 (HER2) and insulin like growth factor receptor (IGFR) as well as mutations in PI3K and mutations and amplifications of Akt or downregulation of PTEN may represent an appropriate way to identify populations that are more likely to show significant benefit from mTOR inhibitors."
reach
"This releases ULK1/2 to activate FIP200, a protein critical for autophagosome formation and autophagy initiation; as an upstream effector of mTOR, Akt can activate mTOR via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR."
reach
"As activation of both p44 and p42 MAPK and Akt inhibits not only apoptosis, but also autophagy via activation of the mammalian target of rapamycin, 34 their activation should be involved in determining the mode of cell death, thus leading to necrosis, but not to apoptosis, after ULMW-HA stimulation."
sparser
"Upon activation by receptor tyrosine kinases or G-protein coupled receptors, AKT activates mTOR, which in turn stimulates protein translation through inhibitory phosphorylation of eukaryotic translational initiation factor eIF4E-binding protein 1 (4E-BP1) that inhibits eIF4E, and activating phosphorylation of p70S6 kinase (S6K) that phosphorylates ribosomal S6 protein."
reach
"Then, in non small cell lung cancer cells, it was shown that DHA induced apoptosis and autophagy were associated to mTOR suppression induced by both AMPK activation and PI3K and Akt inhibition; these data were confirmed in Fat-1 transgenic mice implanted with Lewis lung cancer cells [XREF_BIBR]."
sparser
"The PI3K/AKT/mTOR pathway, the most crucial upstream signalling pathway of autophagy, is well established as a regulator of a wide range of cellular processes that mediate cell survival and death, and this pathway is inhibited by malnutrition, hypoxia, external pressure or other stress conditions to suppress cell proliferation and enhance autophagy, eventually leading to cell death. xref , xref Akt is a member of the serine/threonine protein kinase family and is activated in a PI3K‐dependent manner in response to various stimuli. xref Phosphorylated class I PI3K and Akt activate mTOR. xref mTOR is a downstream target of the PI3K/AKT pathway. xref mTOR kinase is part of two mTOR complexes, mTORC1 and mTORC2, each of which has a different protein component. xref mTORC1 is a major negative regulator of autophagy. xref Inhibition of mTORC1 causes TFEB dephosphorylation and nuclear translocation, which subsequently increases lysosome biogenesis, and affects autophagic flux. xref , xref , xref Suppression of PI3K and Akt signalling inhibits mTOR phosphorylation at Ser2448, thereby inducing autophagy and increasing the levels of autophagy‐related proteins. xref Activation of this pathway promotes cell growth, differentiation and survival while down‐regulating apoptotic signals. xref , xref The ULK1 protein kinase is a key regulator of autophagy initiation and progression. xref In vitro, the mechanical induction of autophagy is TOR independent. xref However, there may be differences between in vivo and in vitro studies."
sparser
"The PI3K enzyme itself antagonizes the tumor-suppressor PTEN, and the loss of PTEN increases glycolysis by activation of AKT and HIF-1. xref AKT stimulates glycolysis by increasing the expression and membrane translocation of glucose transporters, and also by phosphorylation of glycolytic enzymes, such as hexokinase (HK) and phosphofructokinase (PFK). xref , xref Moreover, AKT activates mammalian target of rapamycin (mTOR), which indirectly affects other metabolic pathways by activating HIF-1, even under normoxic conditions. xref Oncogene mutation of Ras activates mTOR via the PI3K-Akt-mTOR signaling pathway, and mTOR promotes glycolysis through inducing HIFs. xref , xref , xref , xref , xref The HIFs are transcription factors that regulate gene expression in response to the cellular environment, specifically in the event of decreased oxygen or hypoxia."
reach
"The subset of genes both upregulated by Akt and dependent on mTOR activity were associated with estrogen receptor negative status, higher grade, increasing tumor size and poor prognosis in multiple patient cohorts; these associations were either not present or not as strong for the Akt induced, mTOR independent genes or for AKT1 expression alone."
reach
"In this report, we provide evidence that in the presence of glucose, exendin-4 stimulates rodent islet cell DNA replication via the activation of ribosomal protein S6 kinase 1 (S6K1) and that this is mediated by the protein kinase B (PKB)-dependent activation of mTOR complex 1 (mTORC1)."
reach
"To ascertain this hypothesis, the PI3K and Akt pathway activity was evaluated by measuring the expression and activation (phosphorylation) of Akt, the main regulator of this pathway but also by measuring the phosphorylation of natural substrates of Akt; considering that Akt is known to directly activates mTOR [XREF_BIBR], we measured the phosphorylation level of mTOR as an indicator of Akt activity."
sparser
"While AKT is activated by phospholipid binding and activation loop phosphorylation at Threonine308 by PDK1 and by phosphorylation within the carboxy terminus at Serine473, mTOR is phosphorylated at Serine2448 via the PI3K-signaling pathway. xref AKT activates the mTOR complex 1 (mTORC1) which in addition to mTOR contains mLST8, PRAS40, and RAPTOR. xref This activation involves phosphorylation of tuberous sclerosis complex 2 (TSC2), which blocks the ability of TSC2 to act as a GTPase-activating protein, thereby allowing accumulation of Rheb-GTP and mTORC1 activation."
sparser
"Upon activation by gene mutation or physiologic receptor stimulation, PI3K recruits AKT, which, in turn, activates its downstream effectors, mTOR and NF-κB, via direct phosphorylation of several mTOR- and NF-κB-pathway components [ xref ], thereby promoting cell survival, proliferation, and anabolic metabolism [ xref , xref ]."
reach
"33 In Sewall 's study investigating the significance of PIK3CA mutations in HPV associated oropharyngeal SCCs, the authors reported that mutant PIK3CA tumors had a distinct protein expression profile within HPV positive oropharyngeal SCCs, and PIK3CA mutations in HPV positive cells were associated with activation of the mTOR, but not AKT, signaling pathway; and HPV positive cells expressing mutant PIK3CA were more sensitive to PIK3CA and mTOR inhibition versus AKT inhibition, implying that inhibitors for mTOR may have activity against HPV positive PIK3CA mutant oropharyngeal cancers."
reach
"The PI3K-AKT-mTOR axis could be considered to be a single pathway [XREF_BIBR] in which AKT activates mTOR to control cell proliferation and growth in response to environmental stimuli by phosphorylating and inactivating the mTOR suppressors tuberous sclerosis protein 1 (TSC1) and TSC2 [XREF_BIBR, XREF_BIBR]."
reach
"Metformin treatment (1) directly (Fig 3-❷), (2) via the inhibition of AKT (Fig 3-❸) and/or (3) activation of AMPK (Fig 3-❹) inhibits the mTOR signaling pathway (Fig 3-❺), thus halting the cellular translational process, which is necessary for the synthesis of host and viral proteins."
reach
"Moreover, in IGF-I- and rapamycin treated cells simultaneously deficient in Akt1 and Akt3, p70S6K phosphorylation was not completely eliminated (XREF_FIG), further suggesting an Akt independent activation of mTOR and p70S6K, as well as rapamycin-insensitive activation of p70S6K under conditions of low Akt abundance in myoblasts."
reach
"The activation of mTOR by Akt also promotes fatty acid (FA) uptake and synthesis by activating transcription factor sterol regulatory binding protein 1C (SREBP-1c) which is a protein that enhances the transcription of FA and triglyceride biosynthetic enzymes [XREF_BIBR, XREF_BIBR]."
sparser
"Besides this, activation of mTOR by AKT can phosphorylate and inactivate 4E-BP1 (for eIF4E-Binding Proteins), a family of small acidic proteins that function as translational repressors of eIF4E. Phosphorylation of 4E-BP1 by mTOR releases 4E-BP1 from eIF4E thereby activating eIF4E involved translation-initiation complex and consequently the translational repertoire of a cell toward malignancy [ xref ]."
reach
"Cytarabine reduced the phosphorylation of the major negative regulator of autophagy, mammalian target of rapamycin (mTOR), and its downstream target p70S6 kinase in REH cells, which was associated with downregulation of mTOR activator Akt and activation of extracellular signal- regulated kinase."