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AKT activates MTOR. 1000 / 2642
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"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."
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"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 "
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"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)."
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"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]."
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"In addition, Akt triggers mechanistic target of rapamycin (mTOR)/mTOR complex 1 (mTORC1) activation, leading to enhanced expression of several glycolytic enzymes such as phosphofructokinase 1 (PFK-1) and thus promoting a metabolic shift from physiologically preferred OXPHOS in PCs towards enhancedglycolysis in malignant PCs (225)."
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"Altogether, these data indicate that the more severe myopathy of mTORmKOKI as compared with mTORmKO mice is due to more robust suppression of muscle mTORC1 signalling associated with stronger alterations in translation and autophagy during postnatal development.Finally, we investigated the phosphorylation of mTOR on S2448, a widely used biomarker in the skeletal muscle biology field to assess mTOR activation.43 PKB/Akt has been initially suggested to directly phosphorylate mTOR on this site,44, 45 while later studies demonstrated that mTOR S2448 is phosphorylated by S6K in a negative feedback loop.46, 47 Interestingly, phosphorylation of mTOR at S2448 was not abolished but rather increased in muscle from mTORmKOKI as compared with control mice at both 4 and 6 weeks of age, despite inhibition of mTORC1 signalling (Figure 4D and Supporting Information, Table S2)."
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"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."
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"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 ]."
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"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 "
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"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."
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"Given that kainate is a glutamate agonist and that large amounts of endogenous glutamate are released during status epilepticus, a rational hypothesis is that stimulation of the Akt and PI3K pathway by glutamate XREF_BIBR, XREF_BIBR and calcium influx during kainate status epilepticus causes the downstream activation of the mTOR pathway (XREF_FIG)."
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"The activated AKT can subsequently activate mammalian target of rapamycin (mTOR) and its downstream signalling molecule p70 ribosomal protein S6 kinase (P70S6K) that can finally have a great role in elevated condition of uncontrolled epidermal cells proliferation (Mercurio et al. xref ; Karagianni et al. xref )."
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"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]."
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"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."
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"CUMS exposure also significantly decreased GSH, BDNF, phosphorylation of AKT, and mTOR in PFC [50, 51, 93], and antioxidant drugs such as resveratrol [93], 5-HT [95], or carvedilol [96] can increase BDNF, AKT, and mTOR and decrease oxidative stress, significantly alleviating depression."
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"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]."
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"The mTOR signaling pathway is composed of protein kinase B (Akt and PKB) as the main upstream mediator and two best characterized downstream effector molecules, ribosomal p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and activated Akt may positively regulate mTOR, leading to increased phosphorylation of S6K1 and 4E-BP1 [XREF_BIBR]."
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"In summary, our outcomes suggested that DHCR24 knock-down obviously increase the activity of GSK3β signaling through PI3-K/Akt signaling.Abnormal activation of mTOR signaling have been recently implicated in the pathophysiology of AD and other neurodegenerative disease, including such as autophagy, tauopathy, and Aβ metabolism (Buller et al., 2008; Bhaskar et al., 2009; Zare-Shahabadi et al., 2015)."
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"BCR co-receptor CD19 and the BCR itself (through SYK kinase) are able to activate PI3K signaling, which leads to activation of AKT which activates downstream mTOR promoting cell survival, again showing the large role BCR signaling plays in promotion of DLBCL (Uddin et al., 2006; Young and Staudt, 2013)."
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"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."
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"In the PPP group, the ratio of phosphorylated IGF1R protein to total protein in MCT4-L929 cells was significantly lower than that in control-L929 cells, which could be attributed to the notable changes in IGF1R and p-IGF1R.SGK1 functions as an essential AKT-independent mediator of the PI3K/mTOR signaling pathway in cancer (62)."
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"This activation leads to the phosphorylation of numerous downstream targets, which include the proapoptotic Bad protein and nuclear factor (NF) κB. Consequently, this impedes apoptosis and enhances cellular survival signaling pathways.The PI3K/Akt pathway also stimulates protein synthesis and cellular growth by activating mammalian target of rapamycin (mTOR)."
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"Because we and others have previously shown that Akt plays a critical role in IPC, XREF_BIBR, XREF_BIBR and that Akt promotes mTOR activity, 24 we can not exclude the possibility that IPC may improve mTOR activity via enhancement of Akt activity and that Akt may be a significant factor in the role of mTOR in IPC."
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"This finding is consistent with previous research showing that the expression of PTEN is down-regulated in HCC cells, while the expression of Akt and mTOR is up-regulated. xref PTEN is a specific protein tyrosine phosphatase and an important tumor suppressor, and negatively regulates and inhibits the Akt/mTOR signaling pathway. xref Akt is one of the most common activated protein kinases in human cancers and is closely related to energy metabolism in cancer cells. xref Meanwhile, Akt activates mTOR by regulating ATP and AMPK activity. xref mTOR, a highly conserved serine–threonine kinase, is an important intracellular energy-sensing molecule that can respond to a variety of nutritional signals. xref "
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"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."
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"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]."
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"Otherwise, expression of sterol regulatory element binding-protein 1c (SREBP-1c) in the de novo lipogenesis pathway can be enhanced through Akt-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) and inhibition of Foxo1, which are both sufficient for de novo lipogenesis ( xref ; xref )."
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"Thereafter, phosphorylated Akt activates mTOR, resulting in phosphorylation of ribosomal protein S6 kinase (p70S6K) and the 4E-binding protein 1 (4E-BP1), which promotes protein synthesis by activating ribosomal protein S6 and releasing eukaryotic translation initiation factor eIF-4E, respectively."
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"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."
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"Alternatively, ethanol activation of PI3K/Akt induces mammalian target of rapamycin (mTOR) complex 1 activity, leading to enhanced rates of synaptic protein synthesis, altered pre- and postsynaptic transmission, and higher ethanol seeking and consumption (Neasta et al., 2014; Weston et al., 2012)."
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"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]."
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"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."
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"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."
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"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."
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"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."
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"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."
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"The activated AKT can subsequently activate mammalian target of rapamycin (mTOR) and its downstream signalling molecule p70 ribosomal protein S6 kinase (P70S6K) that can finally have a great role in elevated condition of uncontrolled epidermal cells proliferation (Mercurio et al. 2021; Karagianni et al. 2022)."
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"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]."
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"PI3K/Akt can also activate the Mammalian target of rapamycin (mTOR), and the PI3K/Akt/mTOR pathway was demonstrated to enhance inflammation, angiogenesis and deposition of ECM in HTS and dysregulation of the PI3K/Akt pathway in skin tissue gives rise to pathological outcomes characterized by excessive proliferation (90, 92)."
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"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 )."
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"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] ."
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"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."
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"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)."
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"As a powerful secondary messenger, PIP3 activates AKT which is also known as protein kinase B. Activated AKT subsequently inhibits the function of the pro-apoptotic protein Bcl-2 family, thereby inhibiting apoptosis. xref In addition, AKT activates mammalian target of rapamycin (mTOR) protein to stimulate cell growth and protein synthesis. xref It is reported that the GDF-15 is an important activator of the PI3K/AKT pathway."
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"The observation that mTOR and p70S6K activation was increased in p110alpha deficient cells (XREF_FIG), and Akt activation is significantly impaired in p110alpha deficient cells (Matheny and Adamo, manuscript in press), suggests that decreases in Akt activation, whether through p110alpha deficiency or Akt deficiency, may provide feedback to an Akt independent mechanism that activates mTOR and p70S6K."
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"The IGF systems consists of multiple circulating ligands (IGF-1, IGF-2 and insulin) interacting with the IGF-1 receptor (IGF-1R) which then leads to signaling through various downstream pathways including the PI3 kinase / Akt pathway inducing stimulation of mTOR and S6 kinase, and activation of the mitogen activated protein kinase (MAPK) pathway through Ras."
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"The PI3K class I family activates the protein kinase B (PKB), also known as AKT, which in turn activates mTOR (mammalian target of rapamycin) (reviewed in [49, 50]) In the hippocampus, cerebral cortex and cerebellum, activation of the AKT/mTOR pathway is essential for neuronal development and synapse formation [51–53] thus contributing to neuronal plasticity and memory [54–56]."
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"Therefore, regulating Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling may inhibit apoptosis of hepatocyte to reduce liver fibrosis and this may be a new anti-fibrosis strategy.12Additionally, PI3K/AKT/mTOR signaling cascade also plays an important role in regulating the proliferation, survival, metabolism of cells and it also regulates the protein synthesis and cell cycle.13,14 In this pathway, PI3K will phosphorylate and activate the AKT protein, which is located on the plasma membrane, following which the AKT protein will activate various downstream pathways to then activate mTOR."
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"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."
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"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]."
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"The findings collected from the murine model presented in this study supported that UC-MSCs exerted inhibitory effect on cell autophagy via the AKT/mTOR signaling pathway, by which the sperm quality of AS rats was partially restored.Based on the preliminary exploration, the sperm quality of rats administered with ORN by gavage was significantly improved after local injection of UC-MSCs into the testicle, accompanied by ameliorated testicular injury caused by ORN in AS rats."
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"AKT can stimulate the translation of milk proteins through its ability to phosphorylate eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), and the AKT-dependent activation of mammalian target of rapamycin (MTOR) stimulates translation through ribosomal protein S6 kinase (S6K1) and eukaryotic translation elongation factor 2."
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"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 ]."
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"Specifically, M1 macrophages are involved in plaque initiation, progression, and instability, whereas M2 macrophages act reversely.[ xref , xref ]On the one hand, AKT activates mTOR in macrophage cells, thereby stimulating histone acetylation and the expression of genes supporting the M2 phenotype.[ xref ]Besides, AKT1 inhibits C/EBPβ to generate the M2 phenotype whereas the deficiency of AKT1 induces M1 cells,[ xref ]which means the balance of AKT isoforms also matters in the network of regulation."
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"Most importantly, there are multiple RTK signalling cascades that contribute to mTor signalling, including the Mek1/2-Erk 1/2-Rsk and PI3K-Akt pathways that either directly activate the mTor pathway, eg through inhibiton of TSC, or indirectly via inhibition of GSK3beta, which is an activator of TSC [XREF_BIBR, XREF_BIBR]."
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"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 ]."
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"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 ]."
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"In addition, further research revealed that TrkB activates the downstream of AKT, also named protein kinase B (PKB) and extracellular regulated protein kinase (ERK) mediated mTOR signaling, suggesting that the phosphorylation of ERK and AKT and activation of the common downstream molecular mTOR participate in the antidepressant-like effects of rapastinel in vivo [38, 39]."
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"Akt mediated inhibition of tuberous sclerosis complex (TSC 1 and 2) then stimulates the mTOR which, in turn, modulates its downstream effectors eIF4E binding protein 1 (4EBP1) and p70S6 kinase to modulate the synthesis of proteins that regulate cell survival, apoptosis, metabolism, proliferation, angiogenesis, glucose uptake, and ribosome biogenesis [97,100,101]."
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"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."
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"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."
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"Many tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), can activate PI3K on the cell surface; subsequently, Akt is recruited to the cell and activates mTOR, which can induce HIF-1 to promote glycolysis in cells [33]."
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"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)."
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"Therefore, AKT functions in the activation of mTOR signaling through both direct phosphorylation of mTOR protein and inhibition of the TSC1/TSC2 complex.Over the past several decades, strenuous efforts have been made in the development of new targeted therapy using small molecule inhibitors against the PI3K/AKT pathway, which specifically targets toward PI3K, AKT, or mTOR."
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"When insulin‐like growth factor 1 (IGF‐1) or insulin binds to IGF‐1 receptors (a tyrosine kinase receptor) on the myocytes, it results in a chain of reactions leading to the phosphorylation of Akt, a cellular kinase. xref Phosphorylated Akt, in turn, phosphorylates and activates mTOR complex 1 (mTORC1), activated mTORC1 stimulates protein synthesis by activating ribosomal protein kinase, which is p70‐S6 kinase 1, and it also inhibits proteolysis by inhibiting autophagy‐activating kinases ULK1/2. xref The FoxO (Forkhead box O) family of transcription factors that have a role in promoting autophagy and maintenance of the ubiquitin‐proteasome system causing cellular apoptosis, Akt phosphorylates members of the FoxO family, which leads to their inhibition. xref Akt also enhances mitochondrial respiration by activating ATP citrate lyase (ACL) leading to increased ATP production, which is essential for protein synthesis in muscle."
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"The PI3K class I family activates the protein kinase B (PKB), also known as AKT, which in turn activates mTOR (mammalian target of rapamycin) (reviewed in [ xref , xref ]) In the hippocampus, cerebral cortex and cerebellum, activation of the AKT/mTOR pathway is essential for neuronal development and synapse formation [ xref – xref ] thus contributing to neuronal plasticity and memory [ xref – xref ]."
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"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 ."
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"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."
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"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."
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"Furthermore, this signaling pathway might serve as a backup to compensate increased PI(3,4,5)P3 levels in the plasma membrane, e.g., in PI3K gain of function or PTEN loss of function mutations, which occur in various types of cancer: increased PI(3,4,5)P3 enhances the activation of PDK1/Akt, which in turn results in the activation of mTOR [57], which is counterbalanced by simultaneous activation of LKB1/AMPK and subsequent inhibition of mTOR by AMPK [58,59]."
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"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."
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"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."
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"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."
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"Head and neck squamous cell carcinomas (HNSCC) are often characterized by overexpression of epidermal growth factor receptor (EGFR), c-Met as well as cytokine and G protein coupled receptors, which converge on PI3K and Akt pathway in turn activating mTOR and positively regulating cap dependent translation."
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"Accordingly, a better understanding of how WNT‐related alterations might affect the translation initiation process in CRC is of great importance.Among the most commonly described mutations found in CRC are alterations in RAS/MAPK and PI3K/AKT pathway members, driving a subsequent activation of mTOR signaling."
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"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 ]."
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"In addition to anti-angiogenic activity via the targeting of endothelial cells, a member of the second generation of targeted therapies for RCC, regorafenib, has been shown to exhibit anti-proliferative activity via inhibition of the mitogen activated protein kinase pathway in cancer cells; 13 however, regorafenib does not address one of the resistance mechanisms of mTOR inhibition in which the PI3K and AKT pathway activates mTOR independent downstream effectors and thereby supports continued tumor growth."
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"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."
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"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."
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"AKT also activates mTORC1 (mammalian target of rapamycin complex 1), which not only regulates mitochondrial oxidative function [43] via stimulation of PGC-1α [44] but also increases the translation of nuclear-encoded mitochondrial proteins via activation of eIF4E (eukaryotic translation initiation factor 4E) [45]."