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immunosupressant and prevents the proliferation of T cells and B cells. Paradoxically, even though rapamycin is a federally approved immunosuppressant, its inhibition of mTORC1 results in better quantity and quality of functional memory T cells. mTORC1 inhibition with rapamycin improves the ability of naΓ―ve T cells to become memory precursor cells during the expansion phase of T cell development . This inhibition also allows for an increase in quality of these memory T cells that become mature T cells during the contraction phase of their development. mTORC1 inhibition with rapamycin has also been linked to a dramatic increase of B cells in old mice, enhancing their immune systems. This paradox of rapamycin inhibiting the immune system response has been linked to several reasons, including its interaction with T-regulatory cells. The mechanisms mTORC1's inhibition on proliferation and differentiation of hematopoietic stem cells has yet to be fully elucidated.
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domains of for
Huntingtin, EF3, A subunit of PP2A, and TOR1. These HEAT repeats are considered to be for protein-protein interactions with either Raptor or Rictor for mTORC1 or mTORC2, respectively. FAT lies downstream of the HEAT region and will interact with the FAT C terminal domain and this interaction is thought to modulate the kinase activity of mTOR. This FATC domain is so conserved that changing one amino acid in this sequence has been shown to disrupt mTOR activity. The FRB (FKB12-rapamycin binding) domain is the stretch of amino acids that rapamycin binds to in order to inhibit mTOR activity. The NR domain is located just before the FATC domain on the C terminus and is a putative negative regulatory region, where substrates can bind to inhibit mTOR activity.
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been shown to be inhibited by rapamycin. The kinase domain is the catalytic domain responsible for phosphorylating serine and threonine residues on target proteins. Attached to the kinase domain is the mLST8 domain, the mammalian ortholog of the LST8 protein first discovered in yeast. mTORc2 has been shown to require this domain for function, and it has been suggested that it is also required in mTORc1. The NR (negative regulatory) domain is the putative negative regulatory region of the mTOR complexes. The FATC domain, or FAT domain on the C-terminus, has been shown to be necessary for the kinase function of mTOR, as a single amino acid deletion from this sequence prevents such activity.
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and diabetes. mTOR consists of two structures, mTOR complex 1 (mTORc1) and mTOR complex 2 (mTORc2). mTORc1, named for its putative sensitivity to rapamycin, is the better-studied component of the mTOR protein and is thought to play the principal role in the initial mTOR protein; it is believed to regulate cell growth, proliferation, and survival by integrating hormones, growth factors, nutrients, stressors, and energy signals. mTORc2 is thought to regulate cytoskeleton and cell survival in response to insulin, although the upstream signaling pathways have yet to be fully elucidated.
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binds to the 5' cap of mRNA and will recruit the helicase eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B (eIF4B). The helicase is required to remove hairpin loops that arise in the 5' untranslated regions of mRNA, that prevent premature translation of proteins. Once the initiation complex is assembled at the 5' cap of mRNA, it will recruit the 40S small ribosomal subunit that is now capable of scanning for the AUG codon start site, because the hairpin loop has been eradicated by the eIF4A helicase.
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GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein GRB2 gets binds with its SH2 domains. This recruits the GEF called Sos, which activates the Ras G protein. Ras activates Raf (MAPKKK), which activates Mek (MAPKK), which activates Erk (MAPK). Erk can go on to activate RSK. Erk will phosphorylate the serine residue 644 on TSC2, while RSK will phosphorylate serine residue 1798 on TSC2. These phosphorylations will cause the heterodimer to fall apart, and not be able to deactivate Rheb. This, thus keeps mTORC1 active.
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GSK3 beta is able to phosphorylate TSC2 on two serine residues of 1341 and 1337, in conjunction with AMPK phosphorylating serine residue 1345. It has been studied that the AMPK is required to first phosphorylate residue 1345 before GSK3 beta can phosphorylate its target serine residues. This phosphorylation of TSC2 would inactivate this complex, if GSK3 beta were active. Since the Wnt pathway inhibits GSK3 signaling, when the Wnt pathway is active, so also is the mTORC1 pathway. Now, mTORC1 can activate protein synthesis for the developing organism.
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active Rheb-GTP activates mTORC1 through unelucidated pathways. Thus, many of the pathways that influence mTORC1 activation do so through the activation or inactivation of the TSC1/TSC2 heterodimer. This control is usually performed through phosphorylation of the complex, which can cause the dimer to dissociate losing its GAP activity, or the phosphorylation can cause the heterodimer to have more active GAP activity, depending on the kinase phosphorylating the dimer.
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can inhibit the insulin RTK via phosphorylation. When this negative feedback loop is no longer there, the upstream regulators of mTORC1 become more active than they would otherwise would have been under normal mTORC1 activity. Another problem is that since mTORC2 is resistant to rapamycin, and it too acts upstream of mTORC1 by activating Akt. Thus signaling upstream of mTORC1 still remains very active upon its inhibition via rapamycin and the rapalogs.
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cortex may accumulate and begin to produce reactive oxygen species. It is important to note that both cancer cells as well as those cells with greater levels of mTORC1 both rely more on glycolysis in the cytosol for ATP production rather than through oxidative phoshphorylation in the inner membrane of the mitochondria.
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Rapamycin was the first known inhibitor of mTORC1, considering that mTORC1 was discovered as being the target of rapamycin. Rapamycin will bind to cytosolic FKBP12 and act as a scaffold molecule, allowing this protein to dock on the FBP regulatory region on mTORC1. The binding of the FKBP12-rapamycin
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Deletion of the TOR1 gene in yeast increases mitochondrial respiration by enhancing the translation of mitochondrial DNA that encodes for the complexes involved in the electron transport chain. When this electron transport chain is not as efficient, the unreduced oxygen molecules in the mitochondrial
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Dietary restriction has been shown to significantly increase lifespan in the human model of Rhesus monkeys as well as protect against their age related decline. More specifically, Rhesus monkeys on a calorie restricted diet had significantly less chance of developing cardiovascular disease, diabetes,
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Mitogens like insulin like growth factor 1 (IGF1) can activate the Ras-ERK pathway, which can control the TSC1/TSC2 complex as well as directly have the same downstream role that mTORC1 has. In this pathway, the G protein Ras is tethered to the plasma membrane via a farnesyl group and is its inactive
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The second generation of inhibitors were created to overcome problems with upstream signaling upon the introduction of first generation inhibitors to the treated cells. One problem with the first generation inhibitors of mTORC1 is that there is a negative feedback loop from phosphorylated S6K, that
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The Wnt pathway is responsible for cellular growth and proliferation during organismal development. Thus it could be reasoned that activation of this pathway also activates mTORC1. Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta (GSK3 beta). When the Wnt pathway is not active,
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In order for translation to take place, abundant sources of energy, particularly in the form of ATP, need to be present. If these levels of ATP are not present, due to its hydrolysis into other forms like AMP, and the ratio of AMP to ATP molecules gets too high, AMPK will become activated. AMPK will
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Because insulin is a factor that is secreted by pancreatic beta cells upon glucose elevation in the blood, this signaling ensures that there is energy for protein synthesis to take place. In a negative feedback loop, S6K-1 is able to phosphorylate the insulin receptor, and inhibit its sensitivity to
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All of these variables for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 complex. TSC2 is a GTP-ase activating protein (GAP). Its GAP activity interacts with Rheb by hydrolyzing the GTP of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The
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Activated mTORC1 will phosphorylate transcription inhibitor 4E-BP1, releasing it from eukaryotic translation initiation factor 4E (eIF4E). eIF4E is now free to join the eukaryotic translation initiation factor 4G (eIF4G) and the eukaryotic translation initiation factor 4A (eIF4A). This complex then
774:
Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Consequentially, mTORC1 signaling is sensitive to amino acid levels in the cell. Studies have shown that depriving amino acid levels inhibits
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When oxygen levels in the cell are low, it will limit its energy expenditure through the inhibition of protein synthesis. Under hypoxic conditions, hypoxia inducible factor one alpha (HIF-1 alpha) will stabilize and activate transcription of REDD1. After translation, this REDD1 protein will bind to
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OR1 amino acid repeats that it contains. The HEAT domain is implicated in protein-protein interactions. The FAT domain I need to research more about. The FRB domain is specifically targeted by rapamycin for inhibition for the mTOR complexes. It is important to note, that only the mTORc1 complex has
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In 1991, a genetic screen was performed on
Saccharomyces cerevisiae to elucidate what rapamycin was specifically targeting to initiate this response. It was found that knockout of three genes allowed for the fungus' resistance to rapamycin. Two of the genes were called targets of rapamycin, or TOR,
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Siroliumus, which is the drug name for rapamycin, was approved by the FDA in 1999 to prevent against host rejection in patients undergoing kidney transplantation. In 2003, it was approved as a stent covering for people who want to widen their arteries to prevent against heart attacks and stuff. In
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The mammalian target of rapamycin (mTOR) is considered a 'master switch' of cellular processes, regulating transcription of proteins required for cell growth and proliferation by sensing energy and nutrient levels. As a result, it plays an important role in various human diseases, including cancer
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Second generation inhibitors are able to bind to the ATP binding site on the kinase domain of the mTOR core protein itself and abolish activity of both mTOR complexes. In addition, since the mTOR and the PI3K proteins are both in the same PIKK family of kinases, some second generation inhibitors
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mTORC1 plays a role in the differentiation and proliferation of hematopoietic stem cells. Its upregulation has been shown to cause premature aging in hematopoietic stem cells. Conversely, inhibiting mTOR restores and regenerates the hematopoietic stem cell line. Rapamycin is used clinically as an
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Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed. Most specifically, carbohydrate consumption activates mTORC1 through the insulin growth factor pathway. In addition, amino acid consumption will stimulate mTORC1 through the
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The mTOR core protein is 2549 amino acids long and contains a HEAT repeats domain, FAT domain, FRB domain, kinase domain, NR domain, and FATC domain. The HEAT domain spans the first half of the core protein and consists of many tandem HEAT repeats which stands for the amino acid sequences for the
620:
made an antifungal, which they named rapamycin after the island's name Rapa Nui, which it was called by the locals meaning "navel of the world." Studies on rapamycin revealed that it was a powerful antifungal agent that could arrest fungal activity at the G1 phase. It was then tested in rats as a
828:
mTOR was found to be related to aging in 2001 when the ortholog of S6K, SCH9, was deleted in S. cerevisiae, doubling its lifespan. As a result, mTORC1 signaling was focused on and techniques used to inhibit its activity in C. elegans, fruitflies, and mice significantly increased their lifespans
816:
Active S6K can bind to the SKAR scaffold protein that can get recruited to exon junction complexes. Exon junction complexes span the mRNA region where two exons come together after an intron has been spliced out. Once S6K binds to this complex, increased translation on these mRNA regions occurs.
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mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level. Because autophagy appears to decline with age, activation of autophagy may help
845:
Conservation of stem cells in the body has been shown to help prevent against premature aging. mTORC1 activity plays a critical role in the growth and proliferation of stem cells. Knocking out mTORC1 results in embryonic lethality due to lack of trophoblast development. Treating stem cells with
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The role of mTOR is to activate translation of proteins. In order for cells to grow and proliferate by manufacturing more proteins, the cells must ensure that they have the resources available for protein production. Thus, for protein production, and therefore mTORC1 activation, cells must have
858:
Autophagy is the major degradation pathway in eukaryotic cells and is essential for the removal of damaged organelles via macroautophagy or proteins and smaller cellular debris via microautophagy from the cytoplasm. Thus, autophagy is a way for the cell to recycle old and damaged materials by
695:
Growth factors like insulin can activate mTORC1 through the receptor tyrosine kinase (RTK) pathway. Ultimately Akt phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462. These phosphorylated sites will recruit the cytosolic anchoring protein 14-3-3 to TSC2,
900:
2007, they began being approved for treatments against cancers such as renal cell carcinoma. In 2008 they were approved for mantle cell lymphoma. mTORC1 inhibitors have recently been approved for treatment of pancreatic cancer. In 2010 they were approved for treatment of tuberous sclerosis.
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Cytokines like tumor necrosis factor alpha (TFNalpha), can induce mTOR activity through IKK beta. IKK beta can phosphorylate TSC1 at serine residue 487 and TSC1 at serine residue 511. This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP bound state.
741:
AMPK can also phosphorylate Raptor on two serine residues. This phosphorylated Raptor now recruits 14-3-3, to bind to it, preventing Raptor from being part of the mTORC1 complex. Since mTORC1 cannot recruit its substrates without Raptor, no protein synthesis via mTORC1 occurs.
882:
Inhibition of mTORC1 has also been shown to increase transcription of the NRF2 gene, which is a transcription factor that is able to regulate the expression of electrophilic response elements as well as antioxidants in response to increased levels of reactive oxygen species.
699:
Akt will also phosphorylate PRAS40, causing it to fall off of Raptor on mTORC1. PRAS40 prevents Raptor from recruiting mTORC1's substrates 4E-BP1 and S6K-1. Thus when PRAS40 falls off of Raptor, the two substrates are recruited to mTORC1 and thereby activated in this way.
862:
Upon activation, mTORC1 will phosphorylate Atg 13, preventing it from entering the ULK1 kinase complex, which consists of Atg1-Atg17-Atg101. This prevents the structure from being recruited to the preautophagosomal structure at the plasma membrane, inhibiting autophagy..
637:
mTORc1 and 2 share the same core protein complex of 2549 amino acids, which contains seven conserved domains, written from the N- to the C- terminus as HEAT, FAT, FRB, kinase, NR, and FATC domains. The largest domain is called the HEAT repeat domain, named for the
779:
heterodimers to switch to its active conformation. Active Rag heterodimers interact with RAPTOR, localizing mTORC1 to the surface of late endosomes and lysosome where the Rag GTPases are located. This allows mTORC1 to physically interact with
621:
potential antifungal drug in humans, and was found to also greatly suppress their immune system by blocking the G1 to S phase transition in T-lymphocytes. This has led to its clinical use as an immunosupressant following organ transplantation.
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Rapamycin itself is not very water soluble and is not very stable, so scientists developed rapamycin analogs, called rapalogs, to overcome these two problems with rapamycin. These drugs are considered the first generation inhibitors of mTOR.
696:
disrupting the TSC1/TSC2 dimer. When TSC2 is not associated with TSC1, TSC2 loses its GAP activity and can no longer hydrolyze Rheb-GTP. This results in continued activation of mTORC1, allowing for protein synthesis via insulin signaling .
812:
S6K also can phosphorylate programmed cell death 4 (PDCD4), which marks it for degradation by ubiquidin ligase Beta-TrCP. PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex.
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AMPK can phosphorylate TSC2 on serine residue 1387, which will now activate the GAP activity of this complex, causing Rheb-GTP to be hydrolyzed into Rheb-GDP. This inactivates mTORC1, and no protein synthesis occurs through this pathway.
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breaking them down into their smaller components, allowing for the resynthesis of newer and healthier cellular structures. Autophagy can thus remove aggregates of proteins and damaged organelles, that can lead to cellular dysfunction.
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while the third gene was already characterized to be Fpr1, which is now known to be a binding protein in the TOR complexes. In 1994, the mammalian target of rapamycin (mTOR) was identified at the rapamycin target in mammals.
784:, which is activated by growth factors such as insulin. The interaction between the Rags and mTORC1 brings mTORC1 to the surface of endosomes and lysosomes where Rheb is located. This is where Rheb-GTP activates mTORC1.
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mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes
4813:
Nashan B, Citterio F (September 2012). "Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature".
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VΓ©zina C, Kudelski A, Sehgal SN (October 1975). "Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle".
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Martelli AM, Evangelisti C, Chappell W; et al. (July 2011). "Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway".
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have dual inhibition towards the mTOR complexes as well as PI3K, which acts upstream of mTORC1. As of 2011, these second generation inhibitors were in phase II of testing.
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De P, Miskimins K, Dey N, Leyland-Jones B (January 2013). "Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: Old targets new hope".
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Hypophosphorylated S6K is located on the eIR3 scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.
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TSC2, which prevents 14-3-3 from inhibiting the TSC complex. Thus, TSC retains its GAP activity towards Rheb, causing Rheb to remain bound to GDP, and mTORC1 inactive.
2852:
Ma XM, Yoon SO, Richardson CJ, JΓΌlich K, Blenis J (April 2008). "SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs".
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Miwa S, Sugimoto N, Yamamoto N; et al. (September 2012). "Caffeine induces apoptosis of osteosarcoma cells by inhibiting AKT/mTOR/S6K, NF-ΞΊB and MAPK pathways".
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Adam-Vizi V (2005). "Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources".
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promote longevity in humans. Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.
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branched chain amino acid/Rag pathway. Thus dietary restriction inhibits mTORC1 signaling through both upstream pathways of mTORC that converge on the lysosome.
5201:"Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes"
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Schmid T, Jansen AP, Baker AR, Hegamyer G, Hagan JP, Colburn NH (March 2008). "Translation inhibitor Pdcd4 is targeted for degradation during tumor promotion".
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Wang H, Zhang Q, Wen Q; et al. (January 2012). "Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway".
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There have been several dietary compounds that have been suggested to inhibit mTOR signaling including EGCG, resveratrol, curcumin, caffeine, and alcohol.
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mTORc1 and mTORc2 both have specific regulatory proteins, known as Raptor and Rictor, respectively. I will go on to talk about Raptor and Rictor next time.
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Due to the lack of synthesis of ATP in the mitochondria under hypoxic stress, AMPK will also become active and thus inhibit mTORC1 through its processes.
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Kaeberlein M, Powers RW, Steffen KK; et al. (November 2005). "Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients".
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mTORC1 will also activate S6K, which is responsible for the recruitment of eIF4B to the initiation complex by phosphorylating its serine residue 422.
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LBK1 is a known tumor suppressor that can activate AMPK. More studies on this aspect of mTORC1 may help shed light on its strong link to cancer.
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Magnuson B, Ekim B, Fingar DC (January 2012). "Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks".
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adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for protein translation to begin.
2071:"Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis"
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Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD (April 2001). "Regulation of longevity and stress resistance by Sch9 in yeast".
4491:"Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth"
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There are two complexes that contain the mTOR core protein: mTOR complex 1 and mTOR complex 2 named mTORC1 and mTORC2 respectively.
4389:"Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression"
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Blagosklonny MV (February 2010). "Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans)".
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Brown EJ, Albers MW, Shin TB; et al. (June 1994). "A mammalian protein targeted by G1-arresting rapamycin-receptor complex".
3322:"Stem cells and ageing. The potential of stem cells to overcome age-related deteriorations of the body in regenerative medicine"
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Tsang CK, Qi H, Liu LF, Zheng XF (February 2007). "Targeting mammalian target of rapamycin (mTOR) for health and diseases".
3469:"Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development"
1664:"The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1"
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Heitman J, Movva NR, Hall MN (August 1991). "Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast".
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Budde K, Gaedeke J (February 2012). "Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition".
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cancer, and age related cognitive decline than those monkeys who were not placed on the calorie restricted diet.
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Reactive oxygen species can damage the DNA and proteins in cells. A majority of them arise in the mitochondria.
3941:"Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease"
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rapamycin will also slow their proliferation, conserving the stem cells in their undifferentiated condition.
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Codogno P, Meijer AJ (November 2005). "Autophagy and signaling: their role in cell survival and cell death".
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RSK has also been shown to phosphorylate Raptor, which helps it overcome the inhibitory effects of PRAS40.
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Apel K, Hirt H (2004). "Reactive oxygen species: metabolism, oxidative stress, and signal transduction".
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Beauchamp EM, Platanias LC (December 2012). "The evolution of the TOR pathway and its role in cancer".
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Lee T, Pelletier J (January 2012). "Eukaryotic initiation factor 4F: a vulnerability of tumor cells".
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The mTORC1 and mTORC2 complexes differ due to the associated proteins that make up their complexes.
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Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (June 2008).
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3388:"mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells"
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Smith SM (June 2012). "Targeting mTOR in mantle cell lymphoma: current and future directions".
4004:"Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks"
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2720:"The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity"
1862:"Context-Dependent Regulation of Autophagy by IKK-NF-ΞΊB Signaling: Impact on the Aging Process"
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There are currently more than 1,300 clinical trials underway for the mTOR complex inhibitors.
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insulin. This has great significance in diabetes mellitus, which is due to insulin resistance.
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Wullschleger S, Loewith R, Hall MN (February 2006). "TOR signaling in growth and metabolism".
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mTOC1 activates transcription and translation through its interactions with 4E-BP1 and S6K.
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Ma XM, Blenis J (May 2009). "Molecular mechanisms of mTOR-mediated translational control".
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5268:"Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR"
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2960:"TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO"
2138:"Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis"
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Raught B, Gingras AC (January 1999). "eIF4E activity is regulated at multiple levels".
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Choi AM, Ryter SW, Levine B (February 2013). "Autophagy in human health and disease".
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complex to the FBP regulatory region inhibits mTORC1 through processes not yet known.
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1002:
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121:
4710:
4386:
4136:
Proud CG (November 2007). "Amino acids and mTOR signalling in anabolic function".
2812:
2566:
1191:"Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony"
5149:
4648:
3818:"An emerging role for TOR signaling in mammalian tissue and stem cell physiology"
2851:
2005:
1405:
988:
528:
379:
238:
97:
17:
4826:
3553:"mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells"
591:
442:
301:
160:
5093:
5058:
5009:
4773:
4695:"Pushing the envelope in the mTOR pathway: the second generation of inhibitors"
4404:
3041:"Rapamycin fed late in life extends lifespan in genetically heterogeneous mice"
2975:
2865:
1927:"The AMPK signalling pathway coordinates cell growth, autophagy and metabolism"
1612:
1440:
1343:
949:
4946:
4086:
3568:
2291:"Wnt signaling pathways in urological cancers: past decades and still growing"
1814:
3632:
3333:
2735:
991:"Mammalian target of rapamycin: a central node of complex signaling cascades"
613:
5284:
5134:"Targeting the mTOR kinase domain: the second generation of mTOR inhibitors"
4507:
4467:
3256:
3133:
2957:
2918:
2373:
2221:"AMP-activated protein kinase, stress responses and cardiovascular diseases"
2154:
1207:
1149:
5443:
5362:
5303:
5234:
5198:
5167:
5101:
5066:
5045:
Fasolo A, Sessa C (2012). "Targeting mTOR pathways in human malignancies".
5017:
4964:
4897:
4834:
4781:
4728:
4656:
4607:
4526:
4475:
4422:
4359:
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4037:
3974:
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3421:
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3274:
3208:
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3074:
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2574:
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2458:
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2324:
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2104:
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1960:
1897:
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1630:
1564:
1546:
1501:
1448:
1413:
1361:
1226:
1069:
1016:
616:
in the 1970s. Researchers studied this sample and found that the bacterium
4001:
3899:
3241:"Caloric restriction delays disease onset and mortality in rhesus monkeys"
2440:
1878:
1275:
1157:
1122:
957:
5216:
4759:
4019:
3200:
1493:
540:
391:
250:
109:
5425:
5407:
4879:
3682:
3056:
2499:
2425:"Spatial regulation of the mTORC1 system in amino acids sensing pathway"
2358:"The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1"
4341:
4149:
3833:
2682:
2236:
1061:
535:
386:
245:
104:
2958:
Robida-Stubbs S, Glover-Cutter K, Lamming DW; et al. (May 2012).
2485:
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Abraham RT, Wiederrecht GJ (1996). "Immunopharmacology of rapamycin".
734:
go on to inhibit energy consuming pathways such as protein synthesis.
2135:
1267:
609:
4861:
4692:
4589:
2086:
1942:
1761:
3119:
4574:"NRF2 and cancer: the good, the bad and the importance of context"
3238:
1426:
4387:
Bonawitz ND, Chatenay-Lapointe M, Pan Y, Shadel GS (April 2007).
2136:
Horak P, Crawford AR, Vadysirisack DD; et al. (March 2010).
2069:
Nagalingam A, Arbiser JL, Bonner MY, Saxena NK, Sharma D (2012).
1987:
1597:"The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation"
4634:
2717:
1990:"AMPK phosphorylation of raptor mediates a metabolic checkpoint"
1661:
516:
367:
226:
85:
3466:
3385:
3038:
989:
Dobashi Y, Watanabe Y, Miwa C, Suzuki S, Koyama S (June 2011).
935:
829:
relative to the control organisms for the respective species.
776:
523:
472:
457:
374:
331:
316:
233:
92:
5348:
3748:
3664:
3467:
Gangloff YG, Mueller M, Dann SG; et al. (November 2004).
4928:
3550:
3319:
3239:
Colman RJ, Anderson RM, Johnson SC; et al. (July 2009).
1988:
Gwinn DM, Shackelford DB, Egan DF; et al. (April 2008).
1047:
190:
175:
49:
34:
3386:
Murakami M, Ichisaka T, Maeda M; et al. (August 2004).
1860:
Salminen A, Hyttinen JM, Kauppinen A, Kaarniranta K (2012).
1253:
1135:
608:
mTOR is considered to be the mammalian target of rapamycin.
5410:"mTOR is a key modulator of ageing and age-related disease"
4002:
Alers S, LΓΆffler AS, Wesselborg S, Stork B (January 2012).
3885:
3815:
2718:
Shahbazian D, Roux PP, Mieulet V; et al. (June 2006).
1662:
Oshiro N, Takahashi R, Yoshino K; et al. (July 2007).
1594:
781:
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5131:
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Harrison DE, Strong R, Sharp ZD; et al. (July 2009).
2288:
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4864:"Everolimus-eluting stents in interventional cardiology"
3751:"The role of mTOR in memory CD8 T-cell differentiation"
3616:"Akt and mTOR in B Cell Activation and Differentiation"
5265:
4068:
2552:
2218:
5266:
Liu M, Wilk SA, Wang A; et al. (November 2010).
4187:"Age-related decline in chaperone-mediated autophagy"
1924:
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4239:
2619:
1188:
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4488:
3938:
3613:
5079:
4931:"mTOR inhibitors in advanced renal cell carcinoma"
4326:"How mitochondria produce reactive oxygen species"
4184:
3667:"mTOR regulates memory CD8 T-cell differentiation"
2668:
5044:
4571:
2422:
1528:
1328:"The complexes of mammalian target of rapamycin"
5127:
5125:
4688:
4686:
4684:
4489:Sun Q, Chen X, Ma J; et al. (March 2011).
3881:
3879:
3744:
3742:
3546:
3544:
3381:
3379:
3234:
3232:
3186:
2284:
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1387:
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1381:
1379:
1377:
1375:
1373:
1371:
1321:
1319:
1317:
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4862:Townsend JC, Rideout P, Steinberg DH (2012).
1799:"Mechanisms of insulin resistance in obesity"
931:
929:
5401:
5342:
5259:
5192:
5122:
5073:
5038:
4989:
4922:
4910:: CS1 maint: multiple names: authors list (
4855:
4806:
4753:
4681:
4628:
4565:
4482:
4447:
4380:
4317:
4282:
4233:
4178:
4129:
4071:"Molecules and their functions in autophagy"
4062:
3995:
3932:
3876:
3809:
3739:
3658:
3607:
3599:: CS1 maint: multiple names: authors list (
3541:
3460:
3376:
3313:
3229:
3180:
3113:
3032:
2951:
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2613:
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2349:
2337:: CS1 maint: multiple names: authors list (
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2117:: CS1 maint: multiple names: authors list (
2062:
1981:
1918:
1910:: CS1 maint: multiple names: authors list (
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5460:) CS1 maint: multiple names: authors list (
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3868:) CS1 maint: multiple names: authors list (
3816:Russell RC, Fang C, Guan KL (August 2011).
3801:) CS1 maint: multiple names: authors list (
3749:Araki K, Youngblood B, Ahmed R (May 2010).
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3533:) CS1 maint: multiple names: authors list (
3452:) CS1 maint: multiple names: authors list (
3368:) CS1 maint: multiple names: authors list (
3320:Ho AD, Wagner W, Mahlknecht U (July 2005).
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5132:Zhang YJ, Duan Y, Zheng XF (April 2011).
4954:
4887:
4718:
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4516:
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4323:
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3411:
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2448:
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2314:
2244:
2163:
2153:
2094:
2013:
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1887:
1877:
1822:
1689:
1679:
1620:
1595:Mendoza MC, Er EE, Blenis J (June 2011).
1554:
1351:
1325:
1216:
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4995:
4303:10.1146/annurev.arplant.55.031903.141701
4135:
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824:mTORC1 Role in Human Diseases and Aging
14:
3551:Chen C, Liu Y, Liu Y, Zheng P (2009).
2429:Acta Biochim. Biophys. Sin. (Shanghai)
1332:Current Protein & Peptide Science
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3957:10.1146/annurev-pathol-020712-163918
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23:
24:
5478:
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2341:) CS1 maint: unflagged free DOI (
2121:) CS1 maint: unflagged free DOI (
1189:Foster KG, Fingar DC (May 2010).
3767:10.1111/j.0105-2896.2010.00898.x
3485:10.1128/MCB.24.21.9508-9516.2004
3404:10.1128/MCB.24.15.6710-6718.2004
1115:10.1146/annurev.immunol.14.1.483
4935:Hematol. Oncol. Clin. North Am
3328:. 6 Spec No (Suppl 1): S35β8.
13:
1:
5456:: CS1 maint: date and year (
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4711:10.1158/1535-7163.MCT-10-0905
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2813:10.1158/0008-5472.CAN-07-1719
2703:: CS1 maint: date and year (
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2634:10.1016/s1357-2725(98)00131-9
2567:10.1016/j.cellsig.2011.08.010
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917:
840:
5150:10.1016/j.drudis.2011.02.008
4998:Best Pract Res Clin Haematol
4649:10.1016/j.drudis.2006.12.008
4495:Proc. Natl. Acad. Sci. U.S.A
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2142:Proc. Natl. Acad. Sci. U.S.A
2006:10.1016/j.molcel.2008.03.003
1406:10.1016/j.devcel.2007.03.020
1326:Zhou, H.; Huang, S. (2010).
853:
7:
5378:Explicit use of et al. in:
5319:Explicit use of et al. in:
4827:10.1097/TP.0b013e3182551021
4542:Explicit use of et al. in:
3716:Explicit use of et al. in:
3518:Explicit use of et al. in:
3437:Explicit use of et al. in:
3290:Explicit use of et al. in:
3157:Explicit use of et al. in:
3090:Explicit use of et al. in:
3009:Explicit use of et al. in:
2769:Explicit use of et al. in:
2590:Explicit use of et al. in:
2523:Explicit use of et al. in:
2189:Explicit use of et al. in:
2039:Explicit use of et al. in:
1715:Explicit use of et al. in:
1291:Explicit use of et al. in:
10:
5483:
5389:CS1 maint: date and year (
5330:CS1 maint: date and year (
5094:10.1053/j.ajkd.2011.10.013
5059:10.2174/138161212800626210
5010:10.1016/j.beha.2012.04.008
4774:10.1016/j.ctrv.2012.12.002
4553:CS1 maint: date and year (
4405:10.1016/j.cmet.2007.02.009
4324:Murphy MP (January 2009).
3727:CS1 maint: date and year (
3529:CS1 maint: date and year (
3448:CS1 maint: date and year (
3301:CS1 maint: date and year (
3168:CS1 maint: date and year (
3101:CS1 maint: date and year (
3020:CS1 maint: date and year (
2976:10.1016/j.cmet.2012.04.007
2866:10.1016/j.cell.2008.02.031
2780:CS1 maint: date and year (
2622:Int. J. Biochem. Cell Biol
2601:CS1 maint: date and year (
2534:CS1 maint: date and year (
2200:CS1 maint: date and year (
2050:CS1 maint: date and year (
1726:CS1 maint: date and year (
1613:10.1016/j.tibs.2011.03.006
1441:10.1016/j.cell.2006.01.016
1344:10.2174/138920310791824093
1302:CS1 maint: date and year (
950:10.7164/antibiotics.28.721
618:Streptomyces hygroscopicus
4947:10.1016/j.hoc.2011.04.008
4087:10.3858/emm.2012.44.2.029
3569:10.1126/scisignal.2000559
1815:10.1007/s11684-013-0262-6
587:
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572:
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522:
510:
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45:
40:
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3633:10.3389/fimmu.2012.00228
3334:10.1038/sj.embor.7400436
2736:10.1038/sj.emboj.7601166
1750:Nat. Rev. Mol. Cell Biol
5285:10.1074/jbc.M110.169284
4508:10.1073/pnas.1014769108
4468:10.1089/ars.2005.7.1140
3257:10.1126/science.1173635
3134:10.1126/science.1115535
2919:10.1126/science.1059497
2374:10.1126/science.1157535
2155:10.1073/pnas.0907705107
1208:10.1074/jbc.R109.094003
1150:10.1126/science.1715094
871:Reactive Oxygen Species
4868:Vasc Health Risk Manag
4456:Antioxid. Redox Signal
4254:10.1038/sj.cdd.4401751
4204:10.1074/jbc.M002102200
2307:10.1186/1476-4598-11-7
1681:10.1074/jbc.M702636200
1547:10.1038/embor.2011.257
3900:10.1056/NEJMra1205406
995:Int J Clin Exp Pathol
5217:10.1210/me.2009-0328
4248:(Suppl 2): 1509β18.
4020:10.1128/MCB.06159-11
3201:10.4161/cc.9.4.10766
1494:10.1038/onc.2012.567
788:Downstream of mTORC1
5426:10.1038/nature11861
4880:10.2147/VHRM.S23388
4291:Annu Rev Plant Biol
4138:Biochem. Soc. Trans
3683:10.1038/nature08155
3057:10.1038/nature08221
2500:10.1038/leu.2011.46
2441:10.1093/abbs/gmr066
1879:10.1155/2012/849541
1797:Ye J (March 2013).
1601:Trends Biochem. Sci
5138:Drug Discov. Today
4637:Drug Discov. Today
4342:10.1042/BJ20081386
4150:10.1042/BST0351187
3834:10.1242/dev.058230
2683:10.4155/fmc.11.150
2368:(5882): 1496β501.
2237:10.1042/CS20110625
1394:Developmental Cell
1103:Annu. Rev. Immunol
1062:10.1042/BJ20110892
678:Upstream of mTORC1
5082:Am. J. Kidney Dis
4762:Cancer Treat. Rev
4242:Cell Death Differ
4144:(Pt 5): 1187β90.
2075:Breast Cancer Res
1488:(34): 3923β3932.
887:mTORC1 Inhibition
650:subunit of PP2A,
604:History/Discovery
601:
600:
597:
596:
452:
451:
448:
447:
311:
310:
307:
306:
170:
169:
166:
165:
5474:
5466:
5465:
5455:
5447:
5437:
5420:(7432): 338β45.
5405:
5399:
5398:
5387:
5381:
5376:
5374:
5366:
5346:
5340:
5339:
5328:
5322:
5317:
5315:
5307:
5297:
5287:
5278:(47): 36387β94.
5263:
5257:
5256:
5246:
5238:
5228:
5196:
5190:
5189:
5179:
5171:
5161:
5129:
5120:
5119:
5113:
5105:
5077:
5071:
5070:
5047:Curr. Pharm. Des
5042:
5036:
5035:
5029:
5021:
4993:
4987:
4986:
4976:
4968:
4958:
4926:
4920:
4919:
4909:
4901:
4891:
4859:
4853:
4852:
4846:
4838:
4810:
4804:
4803:
4793:
4785:
4757:
4751:
4750:
4740:
4732:
4722:
4699:Mol. Cancer Ther
4690:
4679:
4678:
4668:
4660:
4632:
4626:
4625:
4619:
4611:
4601:
4578:Nat. Rev. Cancer
4569:
4563:
4562:
4551:
4545:
4540:
4538:
4530:
4520:
4510:
4486:
4480:
4479:
4462:(9β10): 1140β9.
4451:
4445:
4444:
4434:
4426:
4416:
4384:
4378:
4377:
4371:
4363:
4353:
4321:
4315:
4314:
4286:
4280:
4279:
4273:
4265:
4237:
4231:
4230:
4224:
4216:
4206:
4197:(40): 31505β13.
4182:
4176:
4175:
4169:
4161:
4133:
4127:
4126:
4116:
4108:
4098:
4066:
4060:
4059:
4049:
4041:
4031:
3999:
3993:
3992:
3986:
3978:
3968:
3936:
3930:
3929:
3919:
3911:
3883:
3874:
3873:
3863:
3855:
3845:
3813:
3807:
3806:
3796:
3788:
3778:
3746:
3737:
3736:
3725:
3719:
3714:
3712:
3704:
3694:
3677:(7251): 108β12.
3662:
3656:
3655:
3645:
3635:
3611:
3605:
3604:
3598:
3590:
3580:
3548:
3539:
3538:
3527:
3521:
3516:
3514:
3506:
3496:
3464:
3458:
3457:
3446:
3440:
3435:
3433:
3425:
3415:
3383:
3374:
3373:
3363:
3355:
3345:
3317:
3311:
3310:
3299:
3293:
3288:
3286:
3278:
3268:
3236:
3227:
3226:
3220:
3212:
3184:
3178:
3177:
3166:
3160:
3155:
3153:
3145:
3128:(5751): 1193β6.
3117:
3111:
3110:
3099:
3093:
3088:
3086:
3078:
3068:
3036:
3030:
3029:
3018:
3012:
3007:
3005:
2997:
2987:
2955:
2949:
2948:
2938:
2930:
2913:(5515): 288β90.
2902:
2896:
2895:
2885:
2877:
2849:
2843:
2842:
2832:
2824:
2796:
2790:
2789:
2778:
2772:
2767:
2765:
2757:
2747:
2715:
2709:
2708:
2702:
2694:
2666:
2660:
2659:
2653:
2645:
2617:
2611:
2610:
2599:
2593:
2588:
2586:
2578:
2550:
2544:
2543:
2532:
2526:
2521:
2519:
2511:
2483:
2477:
2476:
2470:
2462:
2452:
2420:
2414:
2413:
2403:
2395:
2385:
2353:
2347:
2346:
2336:
2328:
2318:
2286:
2277:
2276:
2266:
2258:
2248:
2216:
2210:
2209:
2198:
2192:
2187:
2185:
2177:
2167:
2157:
2133:
2127:
2126:
2116:
2108:
2098:
2066:
2060:
2059:
2048:
2042:
2037:
2035:
2027:
2017:
1985:
1979:
1978:
1972:
1964:
1954:
1922:
1916:
1915:
1909:
1901:
1891:
1881:
1857:
1851:
1850:
1844:
1836:
1826:
1794:
1788:
1787:
1781:
1773:
1745:
1736:
1735:
1724:
1718:
1713:
1711:
1703:
1693:
1683:
1674:(28): 20329β39.
1659:
1653:
1652:
1642:
1634:
1624:
1592:
1583:
1582:
1576:
1568:
1558:
1526:
1520:
1519:
1513:
1505:
1477:
1471:
1470:
1460:
1452:
1424:
1418:
1417:
1389:
1366:
1365:
1355:
1323:
1312:
1311:
1300:
1294:
1289:
1287:
1279:
1268:10.1038/369756a0
1251:
1245:
1244:
1238:
1230:
1220:
1210:
1186:
1180:
1179:
1169:
1161:
1133:
1127:
1126:
1098:
1092:
1091:
1081:
1073:
1045:
1039:
1038:
1028:
1020:
1010:
986:
980:
979:
969:
961:
933:
570:
569:
454:
453:
421:
420:
313:
312:
280:
279:
172:
171:
139:
138:
31:
30:
5482:
5481:
5477:
5476:
5475:
5473:
5472:
5471:
5470:
5469:
5449:
5448:
5406:
5402:
5388:
5379:
5377:
5368:
5367:
5347:
5343:
5329:
5320:
5318:
5309:
5308:
5264:
5260:
5240:
5239:
5205:Mol. Endocrinol
5197:
5193:
5173:
5172:
5144:(7β8): 325β31.
5130:
5123:
5107:
5106:
5078:
5074:
5053:(19): 2766β77.
5043:
5039:
5023:
5022:
4994:
4990:
4970:
4969:
4927:
4923:
4903:
4902:
4860:
4856:
4840:
4839:
4815:Transplantation
4811:
4807:
4787:
4786:
4758:
4754:
4734:
4733:
4691:
4682:
4662:
4661:
4643:(3β4): 112β24.
4633:
4629:
4613:
4612:
4590:10.1038/nrc3278
4570:
4566:
4552:
4543:
4541:
4532:
4531:
4501:(10): 4129β34.
4487:
4483:
4452:
4448:
4428:
4427:
4385:
4381:
4365:
4364:
4322:
4318:
4287:
4283:
4267:
4266:
4238:
4234:
4218:
4217:
4183:
4179:
4163:
4162:
4134:
4130:
4110:
4109:
4067:
4063:
4043:
4042:
4008:Mol. Cell. Biol
4000:
3996:
3980:
3979:
3945:Annu Rev Pathol
3937:
3933:
3913:
3912:
3888:N. Engl. J. Med
3884:
3877:
3857:
3856:
3828:(16): 3343β56.
3814:
3810:
3790:
3789:
3747:
3740:
3726:
3717:
3715:
3706:
3705:
3663:
3659:
3612:
3608:
3592:
3591:
3549:
3542:
3528:
3519:
3517:
3508:
3507:
3479:(21): 9508β16.
3473:Mol. Cell. Biol
3465:
3461:
3447:
3438:
3436:
3427:
3426:
3392:Mol. Cell. Biol
3384:
3377:
3357:
3356:
3318:
3314:
3300:
3291:
3289:
3280:
3279:
3251:(5937): 201β4.
3237:
3230:
3214:
3213:
3185:
3181:
3167:
3158:
3156:
3147:
3146:
3118:
3114:
3100:
3091:
3089:
3080:
3079:
3051:(7253): 392β5.
3037:
3033:
3019:
3010:
3008:
2999:
2998:
2956:
2952:
2932:
2931:
2903:
2899:
2879:
2878:
2850:
2846:
2826:
2825:
2797:
2793:
2779:
2770:
2768:
2759:
2758:
2730:(12): 2781β91.
2716:
2712:
2696:
2695:
2671:Future Med Chem
2667:
2663:
2647:
2646:
2618:
2614:
2600:
2591:
2589:
2580:
2579:
2551:
2547:
2533:
2524:
2522:
2513:
2512:
2484:
2480:
2464:
2463:
2421:
2417:
2397:
2396:
2354:
2350:
2330:
2329:
2287:
2280:
2260:
2259:
2217:
2213:
2199:
2190:
2188:
2179:
2178:
2148:(10): 4675β80.
2134:
2130:
2110:
2109:
2087:10.1186/bcr3128
2067:
2063:
2049:
2040:
2038:
2029:
2028:
1986:
1982:
1966:
1965:
1943:10.1038/ncb2329
1923:
1919:
1903:
1902:
1866:Int J Cell Biol
1858:
1854:
1838:
1837:
1795:
1791:
1775:
1774:
1762:10.1038/nrm2672
1746:
1739:
1725:
1716:
1714:
1705:
1704:
1660:
1656:
1636:
1635:
1593:
1586:
1570:
1569:
1527:
1523:
1507:
1506:
1478:
1474:
1454:
1453:
1425:
1421:
1390:
1369:
1324:
1315:
1301:
1292:
1290:
1281:
1280:
1262:(6483): 756β8.
1252:
1248:
1232:
1231:
1201:(19): 14071β7.
1187:
1183:
1163:
1162:
1144:(5022): 905β9.
1134:
1130:
1099:
1095:
1075:
1074:
1046:
1042:
1022:
1021:
987:
983:
963:
962:
934:
927:
922:
889:
873:
856:
843:
826:
668:
22:
21:
20:
18:User:Flemingrjf
12:
11:
5:
5480:
5468:
5467:
5400:
5351:Anticancer Res
5341:
5258:
5191:
5121:
5072:
5037:
4988:
4921:
4854:
4805:
4768:(5): 403β412.
4752:
4705:(3): 395β403.
4680:
4627:
4564:
4481:
4446:
4379:
4316:
4281:
4232:
4177:
4128:
4061:
3994:
3931:
3875:
3808:
3738:
3657:
3606:
3540:
3459:
3398:(15): 6710β8.
3375:
3312:
3228:
3179:
3112:
3031:
2950:
2897:
2844:
2807:(5): 1254β60.
2791:
2710:
2661:
2612:
2545:
2494:(7): 1064β79.
2478:
2415:
2348:
2278:
2231:(12): 555β73.
2211:
2128:
2061:
1980:
1937:(9): 1016β23.
1931:Nat. Cell Biol
1917:
1852:
1789:
1737:
1654:
1584:
1521:
1472:
1419:
1400:(4): 487β502.
1367:
1338:(6): 409β424.
1313:
1246:
1181:
1128:
1093:
1040:
981:
924:
923:
921:
916:
888:
885:
872:
869:
855:
852:
842:
839:
825:
822:
749:Hypoxic Stress
691:Growth Factors
629:mTOR Structure
599:
598:
595:
594:
589:
585:
584:
579:
575:
574:
566:
565:
555:
549:
548:
544:
543:
538:
532:
531:
526:
520:
519:
514:
508:
507:
502:
496:
495:
490:
484:
483:
480:
476:
475:
470:
466:
465:
461:
460:
450:
449:
446:
445:
440:
436:
435:
430:
426:
425:
417:
416:
406:
400:
399:
395:
394:
389:
383:
382:
377:
371:
370:
365:
359:
358:
353:
347:
346:
341:
335:
334:
329:
325:
324:
320:
319:
309:
308:
305:
304:
299:
295:
294:
289:
285:
284:
276:
275:
265:
259:
258:
254:
253:
248:
242:
241:
236:
230:
229:
224:
218:
217:
212:
206:
205:
200:
194:
193:
188:
184:
183:
179:
178:
168:
167:
164:
163:
158:
154:
153:
148:
144:
143:
135:
134:
124:
118:
117:
113:
112:
107:
101:
100:
95:
89:
88:
83:
77:
76:
71:
65:
64:
59:
53:
52:
47:
43:
42:
38:
37:
15:
9:
6:
4:
3:
2:
5479:
5463:
5459:
5453:
5445:
5441:
5436:
5431:
5427:
5423:
5419:
5415:
5411:
5404:
5396:
5392:
5385:
5380:|author=
5372:
5364:
5360:
5357:(9): 3643β9.
5356:
5352:
5345:
5337:
5333:
5326:
5321:|author=
5313:
5305:
5301:
5296:
5291:
5286:
5281:
5277:
5273:
5272:J. Biol. Chem
5269:
5262:
5254:
5250:
5244:
5236:
5232:
5227:
5222:
5218:
5214:
5211:(4): 766β78.
5210:
5206:
5202:
5195:
5187:
5183:
5177:
5169:
5165:
5160:
5155:
5151:
5147:
5143:
5139:
5135:
5128:
5126:
5117:
5111:
5103:
5099:
5095:
5091:
5088:(2): 276β83.
5087:
5083:
5076:
5068:
5064:
5060:
5056:
5052:
5048:
5041:
5033:
5027:
5019:
5015:
5011:
5007:
5004:(2): 175β83.
5003:
4999:
4992:
4984:
4980:
4974:
4966:
4962:
4957:
4952:
4948:
4944:
4941:(4): 835β52.
4940:
4936:
4932:
4925:
4917:
4913:
4907:
4899:
4895:
4890:
4885:
4881:
4877:
4873:
4869:
4865:
4858:
4850:
4844:
4836:
4832:
4828:
4824:
4821:(6): 547β61.
4820:
4816:
4809:
4801:
4797:
4791:
4783:
4779:
4775:
4771:
4767:
4763:
4756:
4748:
4744:
4738:
4730:
4726:
4721:
4716:
4712:
4708:
4704:
4700:
4696:
4689:
4687:
4685:
4676:
4672:
4666:
4658:
4654:
4650:
4646:
4642:
4638:
4631:
4623:
4617:
4609:
4605:
4600:
4595:
4591:
4587:
4584:(8): 564β71.
4583:
4579:
4575:
4568:
4560:
4556:
4549:
4544:|author=
4536:
4528:
4524:
4519:
4514:
4509:
4504:
4500:
4496:
4492:
4485:
4477:
4473:
4469:
4465:
4461:
4457:
4450:
4442:
4438:
4432:
4424:
4420:
4415:
4410:
4406:
4402:
4399:(4): 265β77.
4398:
4394:
4390:
4383:
4375:
4369:
4361:
4357:
4352:
4347:
4343:
4339:
4335:
4331:
4327:
4320:
4312:
4308:
4304:
4300:
4296:
4292:
4285:
4277:
4271:
4263:
4259:
4255:
4251:
4247:
4243:
4236:
4228:
4222:
4214:
4210:
4205:
4200:
4196:
4192:
4191:J. Biol. Chem
4188:
4181:
4173:
4167:
4159:
4155:
4151:
4147:
4143:
4139:
4132:
4124:
4120:
4114:
4106:
4102:
4097:
4092:
4088:
4084:
4080:
4076:
4075:Exp. Mol. Med
4072:
4065:
4057:
4053:
4047:
4039:
4035:
4030:
4025:
4021:
4017:
4013:
4009:
4005:
3998:
3990:
3984:
3976:
3972:
3967:
3962:
3958:
3954:
3950:
3946:
3942:
3935:
3927:
3923:
3917:
3909:
3905:
3901:
3897:
3894:(7): 651β62.
3893:
3889:
3882:
3880:
3871:
3867:
3861:
3853:
3849:
3844:
3839:
3835:
3831:
3827:
3823:
3819:
3812:
3804:
3800:
3794:
3786:
3782:
3777:
3772:
3768:
3764:
3761:(1): 234β43.
3760:
3756:
3752:
3745:
3743:
3734:
3730:
3723:
3718:|author=
3710:
3702:
3698:
3693:
3688:
3684:
3680:
3676:
3672:
3668:
3661:
3653:
3649:
3644:
3639:
3634:
3629:
3625:
3621:
3620:Front Immunol
3617:
3610:
3602:
3596:
3588:
3584:
3579:
3574:
3570:
3566:
3562:
3558:
3554:
3547:
3545:
3536:
3532:
3525:
3520:|author=
3512:
3504:
3500:
3495:
3490:
3486:
3482:
3478:
3474:
3470:
3463:
3455:
3451:
3444:
3439:|author=
3431:
3423:
3419:
3414:
3409:
3405:
3401:
3397:
3393:
3389:
3382:
3380:
3371:
3367:
3361:
3353:
3349:
3344:
3339:
3335:
3331:
3327:
3323:
3316:
3308:
3304:
3297:
3292:|author=
3284:
3276:
3272:
3267:
3262:
3258:
3254:
3250:
3246:
3242:
3235:
3233:
3224:
3218:
3210:
3206:
3202:
3198:
3194:
3190:
3183:
3175:
3171:
3164:
3159:|author=
3151:
3143:
3139:
3135:
3131:
3127:
3123:
3116:
3108:
3104:
3097:
3092:|author=
3084:
3076:
3072:
3067:
3062:
3058:
3054:
3050:
3046:
3042:
3035:
3027:
3023:
3016:
3011:|author=
3003:
2995:
2991:
2986:
2981:
2977:
2973:
2970:(5): 713β24.
2969:
2965:
2961:
2954:
2946:
2942:
2936:
2928:
2924:
2920:
2916:
2912:
2908:
2901:
2893:
2889:
2883:
2875:
2871:
2867:
2863:
2860:(2): 303β13.
2859:
2855:
2848:
2840:
2836:
2830:
2822:
2818:
2814:
2810:
2806:
2802:
2795:
2787:
2783:
2776:
2771:|author=
2763:
2755:
2751:
2746:
2741:
2737:
2733:
2729:
2725:
2721:
2714:
2706:
2700:
2692:
2688:
2684:
2680:
2676:
2672:
2665:
2657:
2651:
2643:
2639:
2635:
2631:
2627:
2623:
2616:
2608:
2604:
2597:
2592:|author=
2584:
2576:
2572:
2568:
2564:
2560:
2556:
2549:
2541:
2537:
2530:
2525:|author=
2517:
2509:
2505:
2501:
2497:
2493:
2489:
2482:
2474:
2468:
2460:
2456:
2451:
2446:
2442:
2438:
2434:
2430:
2426:
2419:
2411:
2407:
2401:
2393:
2389:
2384:
2379:
2375:
2371:
2367:
2363:
2359:
2352:
2344:
2340:
2334:
2326:
2322:
2317:
2312:
2308:
2304:
2300:
2296:
2292:
2285:
2283:
2274:
2270:
2264:
2256:
2252:
2247:
2242:
2238:
2234:
2230:
2226:
2222:
2215:
2207:
2203:
2196:
2191:|author=
2183:
2175:
2171:
2166:
2161:
2156:
2151:
2147:
2143:
2139:
2132:
2124:
2120:
2114:
2106:
2102:
2097:
2092:
2088:
2084:
2080:
2076:
2072:
2065:
2057:
2053:
2046:
2041:|author=
2033:
2025:
2021:
2016:
2011:
2007:
2003:
2000:(2): 214β26.
1999:
1995:
1991:
1984:
1976:
1970:
1962:
1958:
1953:
1948:
1944:
1940:
1936:
1932:
1928:
1921:
1913:
1907:
1899:
1895:
1890:
1885:
1880:
1875:
1871:
1867:
1863:
1856:
1848:
1842:
1834:
1830:
1825:
1820:
1816:
1812:
1808:
1804:
1800:
1793:
1785:
1779:
1771:
1767:
1763:
1759:
1756:(5): 307β18.
1755:
1751:
1744:
1742:
1733:
1729:
1722:
1717:|author=
1709:
1701:
1697:
1692:
1687:
1682:
1677:
1673:
1669:
1668:J. Biol. Chem
1665:
1658:
1650:
1646:
1640:
1632:
1628:
1623:
1618:
1614:
1610:
1606:
1602:
1598:
1591:
1589:
1580:
1574:
1566:
1562:
1557:
1552:
1548:
1544:
1540:
1536:
1532:
1525:
1517:
1511:
1503:
1499:
1495:
1491:
1487:
1483:
1476:
1468:
1464:
1458:
1450:
1446:
1442:
1438:
1435:(3): 471β84.
1434:
1430:
1423:
1415:
1411:
1407:
1403:
1399:
1395:
1388:
1386:
1384:
1382:
1380:
1378:
1376:
1374:
1372:
1363:
1359:
1354:
1349:
1345:
1341:
1337:
1333:
1329:
1322:
1320:
1318:
1309:
1305:
1298:
1293:|author=
1285:
1277:
1273:
1269:
1265:
1261:
1257:
1250:
1242:
1236:
1228:
1224:
1219:
1214:
1209:
1204:
1200:
1196:
1195:J. Biol. Chem
1192:
1185:
1177:
1173:
1167:
1159:
1155:
1151:
1147:
1143:
1139:
1132:
1124:
1120:
1116:
1112:
1108:
1104:
1097:
1089:
1085:
1079:
1071:
1067:
1063:
1059:
1055:
1051:
1044:
1036:
1032:
1026:
1018:
1014:
1009:
1004:
1001:(5): 476β95.
1000:
996:
992:
985:
977:
973:
967:
959:
955:
951:
947:
944:(10): 721β6.
943:
939:
932:
930:
925:
920:
915:
912:
909:
905:
901:
897:
893:
884:
880:
876:
868:
864:
860:
851:
847:
838:
834:
830:
821:
818:
814:
810:
807:
806:
802:
798:
797:
793:
790:
789:
785:
783:
778:
772:
771:
767:
763:
762:
758:
755:
751:
750:
746:
743:
739:
735:
731:
730:
729:Energy Status
726:
722:
721:
717:
714:
710:
709:
705:
701:
697:
693:
692:
688:
684:
680:
679:
675:
674:
670:
666:
663:
659:
656:
653:
649:
645:
641:
635:
631:
630:
626:
622:
619:
615:
614:Easter Island
611:
606:
605:
593:
590:
586:
583:
580:
576:
571:
567:
564:
563:
559:
556:
554:
550:
545:
542:
539:
537:
533:
530:
527:
525:
521:
518:
515:
513:
509:
506:
503:
501:
497:
494:
491:
489:
485:
481:
477:
474:
471:
467:
462:
459:
455:
444:
441:
437:
434:
431:
427:
422:
418:
415:
414:
410:
407:
405:
401:
396:
393:
390:
388:
384:
381:
378:
376:
372:
369:
366:
364:
360:
357:
354:
352:
348:
345:
342:
340:
336:
333:
330:
326:
321:
318:
314:
303:
300:
296:
293:
290:
286:
281:
277:
274:
273:
269:
266:
264:
260:
255:
252:
249:
247:
243:
240:
237:
235:
231:
228:
225:
223:
219:
216:
213:
211:
207:
204:
201:
199:
195:
192:
189:
185:
180:
177:
173:
162:
159:
155:
152:
149:
145:
140:
136:
133:
132:
128:
125:
123:
119:
114:
111:
108:
106:
102:
99:
96:
94:
90:
87:
84:
82:
78:
75:
72:
70:
66:
63:
60:
58:
54:
51:
48:
44:
39:
36:
32:
29:
28:
19:
5452:cite journal
5417:
5413:
5403:
5371:cite journal
5354:
5350:
5344:
5312:cite journal
5275:
5271:
5261:
5243:cite journal
5208:
5204:
5194:
5176:cite journal
5141:
5137:
5110:cite journal
5085:
5081:
5075:
5050:
5046:
5040:
5026:cite journal
5001:
4997:
4991:
4973:cite journal
4938:
4934:
4924:
4906:cite journal
4871:
4867:
4857:
4843:cite journal
4818:
4814:
4808:
4790:cite journal
4765:
4761:
4755:
4737:cite journal
4702:
4698:
4665:cite journal
4640:
4636:
4630:
4616:cite journal
4581:
4577:
4567:
4535:cite journal
4498:
4494:
4484:
4459:
4455:
4449:
4431:cite journal
4396:
4392:
4382:
4368:cite journal
4333:
4329:
4319:
4294:
4290:
4284:
4270:cite journal
4245:
4241:
4235:
4221:cite journal
4194:
4190:
4180:
4166:cite journal
4141:
4137:
4131:
4113:cite journal
4081:(2): 73β80.
4078:
4074:
4064:
4046:cite journal
4011:
4007:
3997:
3983:cite journal
3948:
3944:
3934:
3916:cite journal
3891:
3887:
3860:cite journal
3825:
3821:
3811:
3793:cite journal
3758:
3755:Immunol. Rev
3754:
3709:cite journal
3674:
3670:
3660:
3623:
3619:
3609:
3595:cite journal
3563:(98): ra75.
3560:
3556:
3511:cite journal
3476:
3472:
3462:
3430:cite journal
3395:
3391:
3360:cite journal
3325:
3315:
3283:cite journal
3248:
3244:
3217:cite journal
3195:(4): 683β8.
3192:
3188:
3182:
3150:cite journal
3125:
3121:
3115:
3083:cite journal
3048:
3044:
3034:
3002:cite journal
2967:
2963:
2953:
2935:cite journal
2910:
2906:
2900:
2882:cite journal
2857:
2853:
2847:
2829:cite journal
2804:
2800:
2794:
2762:cite journal
2727:
2723:
2713:
2699:cite journal
2677:(1): 19β31.
2674:
2670:
2664:
2650:cite journal
2628:(1): 43β57.
2625:
2621:
2615:
2583:cite journal
2561:(1): 17β24.
2558:
2555:Cell. Signal
2554:
2548:
2516:cite journal
2491:
2487:
2481:
2467:cite journal
2435:(9): 671β9.
2432:
2428:
2418:
2400:cite journal
2365:
2361:
2351:
2333:cite journal
2298:
2294:
2263:cite journal
2228:
2224:
2214:
2182:cite journal
2145:
2141:
2131:
2113:cite journal
2078:
2074:
2064:
2032:cite journal
1997:
1993:
1983:
1969:cite journal
1934:
1930:
1920:
1906:cite journal
1869:
1865:
1855:
1841:cite journal
1809:(1): 14β24.
1806:
1802:
1792:
1778:cite journal
1753:
1749:
1708:cite journal
1671:
1667:
1657:
1639:cite journal
1607:(6): 320β8.
1604:
1600:
1573:cite journal
1541:(2): 121β8.
1538:
1534:
1524:
1510:cite journal
1485:
1481:
1475:
1457:cite journal
1432:
1428:
1422:
1397:
1393:
1335:
1331:
1284:cite journal
1259:
1255:
1249:
1235:cite journal
1198:
1194:
1184:
1166:cite journal
1141:
1137:
1131:
1106:
1102:
1096:
1078:cite journal
1053:
1049:
1043:
1025:cite journal
998:
994:
984:
966:cite journal
941:
937:
918:
913:
910:
906:
902:
898:
894:
890:
881:
877:
874:
865:
861:
857:
848:
844:
835:
831:
827:
819:
815:
811:
808:
804:
803:
799:
795:
794:
791:
787:
786:
773:
769:
768:
764:
760:
759:
756:
752:
748:
747:
744:
740:
736:
732:
728:
727:
723:
719:
718:
715:
711:
707:
706:
702:
698:
694:
690:
689:
685:
681:
677:
676:
672:
671:
667:
664:
660:
657:
651:
647:
643:
639:
636:
632:
628:
627:
623:
607:
603:
602:
560:
479:Alt. symbols
411:
270:
129:
26:
25:
4874:: 393β404.
4336:(1): 1β13.
4014:(1): 2β11.
3822:Development
2295:Mol. Cancer
1109:: 483β510.
1056:(1): 1β21.
938:J. Antibiot
777:Rag GTPases
770:Amino Acids
761:Wnt Pathway
642:untingtin,
582:Swiss-model
464:Identifiers
433:Swiss-model
323:Identifiers
292:Swiss-model
182:Identifiers
151:Swiss-model
41:Identifiers
4393:Cell Metab
4330:Biochem. J
4297:: 373β99.
3951:: 105β37.
3557:Sci Signal
3189:Cell Cycle
2964:Cell Metab
2801:Cancer Res
2081:(1): R35.
1872:: 849541.
1050:Biochem. J
919:References
841:Stem Cells
578:Structures
573:Search for
547:Other data
429:Structures
424:Search for
398:Other data
288:Structures
283:Search for
257:Other data
147:Structures
142:Search for
116:Other data
2225:Clin. Sci
1994:Mol. Cell
1803:Front Med
854:Autophagy
720:Cytokines
610:Rapamycin
529:NM_022783
488:NCBI gene
380:NM_032375
339:NCBI gene
239:NM_022372
198:NCBI gene
98:NM_020761
57:NCBI gene
5444:23325216
5363:22993301
5304:20851890
5235:20203102
5168:21333749
5102:22130643
5067:22475451
5018:22687453
4965:21763970
4898:22910420
4835:22941182
4782:23352077
4729:21216931
4657:17275731
4608:22810811
4527:21325052
4476:16115017
4423:17403371
4360:19061483
4311:15377225
4262:16247498
4213:10806201
4158:17956308
4105:22257882
4038:22025673
3975:23072311
3908:23406030
3852:21791526
3785:20536567
3701:19543266
3652:22888331
3587:19934433
3503:15485918
3422:15254238
3352:15995659
3326:EMBO Rep
3275:19590001
3209:20139716
3142:16293764
3075:19587680
2994:22560223
2927:11292860
2874:18423201
2821:18296647
2754:16763566
2691:22168162
2642:10216943
2575:21906675
2508:21436840
2488:Leukemia
2459:21785113
2392:18497260
2325:22325146
2255:22390198
2174:20176937
2105:22353783
2024:18439900
1961:21892142
1898:22899934
1833:23471659
1770:19339977
1700:17517883
1631:21531565
1565:22240970
1535:EMBO Rep
1502:23246968
1482:Oncogene
1449:16469695
1414:17419990
1362:20491627
1227:20231296
1070:22168436
1017:21738819
708:Mitogens
592:InterPro
443:InterPro
302:InterPro
161:InterPro
5435:3687363
5295:2978567
5226:5417537
5159:3073023
4956:3587783
4889:3402052
4720:3413411
4599:3836441
4518:3054028
4414:3460550
4351:2605959
4096:3296815
4029:3255710
3966:3971121
3843:3143559
3776:3760155
3692:2710807
3643:3412259
3626:: 228.
3578:4020596
3343:1369281
3266:2812811
3245:Science
3122:Science
3066:2786175
2985:3348514
2907:Science
2745:1500846
2450:3160786
2383:2475333
2362:Science
2316:3293036
2246:3367961
2165:2842042
2096:3496153
2015:2674027
1952:3249400
1889:3412117
1824:3936017
1691:3199301
1622:3112285
1556:3271343
1353:2928868
1276:8008069
1218:2863215
1158:1715094
1138:Science
1123:8717522
1008:3127069
958:1102508
588:Domains
536:UniProt
439:Domains
409:Chr. 19
387:UniProt
298:Domains
268:Chr. 16
246:UniProt
157:Domains
127:Chr. 17
105:UniProt
5442:
5432:
5414:Nature
5361:
5302:
5292:
5233:
5223:
5166:
5156:
5100:
5065:
5016:
4963:
4953:
4896:
4886:
4833:
4780:
4727:
4717:
4655:
4606:
4596:
4525:
4515:
4474:
4421:
4411:
4358:
4348:
4309:
4260:
4211:
4156:
4103:
4093:
4036:
4026:
3973:
3963:
3906:
3850:
3840:
3783:
3773:
3699:
3689:
3671:Nature
3650:
3640:
3585:
3575:
3501:
3494:522282
3491:
3420:
3413:444840
3410:
3350:
3340:
3273:
3263:
3207:
3140:
3073:
3063:
3045:Nature
2992:
2982:
2925:
2872:
2819:
2752:
2742:
2724:EMBO J
2689:
2640:
2573:
2506:
2457:
2447:
2390:
2380:
2323:
2313:
2253:
2243:
2172:
2162:
2103:
2093:
2022:
2012:
1959:
1949:
1896:
1886:
1831:
1821:
1768:
1698:
1688:
1629:
1619:
1563:
1553:
1500:
1447:
1412:
1360:
1350:
1274:
1256:Nature
1225:
1215:
1156:
1121:
1068:
1015:
1005:
956:
796:4E-BP1
673:mTORC1
562:q24.12
558:Chr. 8
541:Q8TB45
524:RefSeq
517:612974
482:DEPDC6
473:DEPTOR
469:Symbol
458:DEPTOR
413:q13.33
392:Q96B36
375:RefSeq
368:610221
332:AKT1S1
328:Symbol
251:Q9BVC4
234:RefSeq
227:612190
187:Symbol
110:Q8N122
93:RefSeq
86:607130
46:Symbol
35:Raptor
2301:: 7.
553:Locus
505:22953
493:64798
404:Locus
356:28426
344:84335
272:p13.3
263:Locus
215:24825
203:64223
191:MLST8
176:MLST8
131:q25.3
122:Locus
74:30287
62:57521
50:RPTOR
16:<
5462:link
5458:link
5440:PMID
5395:link
5391:link
5384:help
5359:PMID
5336:link
5332:link
5325:help
5300:PMID
5253:link
5249:link
5231:PMID
5186:link
5182:link
5164:PMID
5116:link
5098:PMID
5063:PMID
5032:link
5014:PMID
4983:link
4979:link
4961:PMID
4916:link
4912:link
4894:PMID
4849:link
4831:PMID
4800:link
4796:link
4778:PMID
4747:link
4743:link
4725:PMID
4675:link
4671:link
4653:PMID
4622:link
4604:PMID
4559:link
4555:link
4548:help
4523:PMID
4472:PMID
4441:link
4437:link
4419:PMID
4374:link
4356:PMID
4307:PMID
4276:link
4258:PMID
4227:link
4209:PMID
4172:link
4154:PMID
4123:link
4119:link
4101:PMID
4056:link
4052:link
4034:PMID
3989:link
3971:PMID
3926:link
3922:link
3904:PMID
3870:link
3866:link
3848:PMID
3803:link
3799:link
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