mTORC1 - Knowledge

423: 730:). When the Wnt pathway is not active, GSK3B is able to phosphorylate TSC2 on Ser1341 and Ser1337 in conjunction with AMPK phosphorylation of Ser1345. It has been found that the AMPK is required to first phosphorylate Ser1345 before GSK3B can phosphorylate its target serine residues. This phosphorylation of TSC2 would activate this complex, if GSK3B were active. Since the Wnt pathway inhibits GSK3 signaling, the active Wnt pathway is also involved in the mTORC1 pathway. Thus, mTORC1 can activate 558: 829: 8993: 33: 1190:. Its upregulation has been shown to cause premature aging in hematopoietic stem cells. Conversely, inhibiting mTOR restores and regenerates the hematopoietic stem cell line. The mechanisms of mTORC1's inhibition on proliferation and differentiation of hematopoietic stem cells has yet to be fully elucidated. 413:

The role of mTORC1 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

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on the surface of the lysosome in response to amino acid levels in the cell. 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. Studies have shown that depriving amino acid levels inhibits

1130:. When this electron transport chain is not as efficient, the unreduced oxygen molecules in the mitochondrial 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 468:

of the complex. This phosphorylation can cause the dimer to dissociate and lose its GAP activity, or the phosphorylation can cause the heterodimer to have increased GAP activity, depending on which amino acid residue becomes phosphorylated. Thus, the signals that influence mTORC1 activity do so

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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

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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. Rapamycin and its analogues also have procoagulant side effects caused by off-target binding of the

848:(eIF4E) binding protein 1, primarily via phosphorylation and dephosphorylation of its downstream targets. S6K1 and 4E-BP1 modulate translation in eukaryotic cells. Their signaling will converge at the translation initiation complex on the 5' end of mRNA, and thus activate translation. 1511:

The third generation of inhibitors were created following the realization that many of the side effects of rapamycin and rapamycin analogs were mediated not as a result of direct inhibition of mTORC1, but as a consequence of off-target inhibition of mTORC2. Rapamycin analogs such as

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where the Rheb-GTP is located. This allows mTORC1 to physically interact with Rheb. Thus the amino acid pathway as well as the growth factor/energy pathway converge on endosomes and lysosomes. Thus the Ragulator-Rag complex recruits mTORC1 to lysosomes to interact with Rheb.

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AMPK can also phosphorylate Raptor on two serine residues. This phosphorylated Raptor recruits 14-3-3 to bind to it and prevents Raptor from being part of the mTORC1 complex. Since mTORC1 cannot recruit its substrates without Raptor, no protein synthesis via mTORC1 occurs.

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of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The 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

986:, fruitflies, and mice. Inhibition of mTORC1 showed significantly increased lifespans in all model species. Disrupting the gut microbiota of infant mice was found to lead to reduced longevity with signaling of mTORC1 implicated as a potential mechanism. 591:

to TSC2, 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.

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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

681:. 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 prevent it from deactivating Rheb, which keeps mTORC1 active. 1366:

molecule, allowing this protein to dock on the FRB regulatory region (FKBP12-Rapamycin Binding region/domain) on mTORC1. The binding of the FKBP12-rapamycin complex to the FRB regulatory region inhibits mTORC1 through processes not yet known.

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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

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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. These other inhibitors include

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pathway. In addition, amino acid consumption will stimulate mTORC1 through the branched chain amino acid/Rag pathway. Thus dietary restriction inhibits mTORC1 signaling through both upstream pathways of mTORC that converge on the

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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

1025:. Thus, autophagy is a way for the cell to recycle old and damaged materials by breaking them down into their smaller components, allowing for the resynthesis of newer and healthier cellular structures. Autophagy can thus remove 817:. After translation, this REDD1 protein will bind to 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 to be inactive. 781:

AMPK can phosphorylate TSC2 on serine residue 1387, which activates the GAP activity of this complex, causing Rheb-GTP to be hydrolyzed into Rheb-GDP. This inactivates mTORC1 and blocks protein synthesis through this pathway.

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S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites thr-2446 and ser-2448; phosphorylation at these sites appears to stimulate mTOR activity.

708:) signaling pathway essential in stress signaling pathways relating to gene expression, neuronal development, and cell survival. Recent studies have shown there is a direct molecular interaction where JNK phosphorylates 908:

Previous studies suggest that S6K signaling is mediated by mTOR in a rapamycin-dependent manner wherein S6K is displaced from the eIF3 complex upon binding of mTOR with eIF3. Hypophosphorylated S6K is located on the

1495:(PIKK) family of kinases, some second generation inhibitors 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 712:

at Ser-696, Thr-706, and Ser-863. Therefore, mTORC1 activity is JNK-dependent. Thus, JNK activation plays a role in protein synthesis via subsequent downstream effectors of mTORC1 such as S6 kinase and eIFs.

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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

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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

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Though AMPK induced eNOS has been shown to regulate mTORC1 in endothelium. Unlike the other cell type in endothelium eNOS induced mTORC1 and this pathway is required for mitochondrial biogenesis.

1516:, that are more selective for mTORC1 than sirolimus, have been developed and in mice have reduced side effects. mTORC1 inhibitors that have novel mechanisms of action, for example peptides like 1323:. The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine. 753:. 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. 6856: 7141: 381:. This complex embodies the classic functions of mTOR, namely as a nutrient/energy/redox sensor and controller of protein synthesis. The activity of this complex is regulated by 1068:, a cytosolic lectin, which recognizes damaged lysosomal membranes by binding to the exposed glycoconjugates normally facing lysosomal lumen. Under homeostatic conditions, 982:, doubling its lifespan. This greatly increased the interest in upstream signaling and mTORC1. Studies in inhibiting mTORC1 were thus performed on the model organisms of 1491:

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

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Rapamycin is used clinically as an immunosuppressant and prevents the proliferation of T cells and B cells. Paradoxically, even though rapamycin is a federally approved

6295:Śledź KM, Moore SF, Durrant TN, et al. (July 2020). "Rapamycin restrains platelet procoagulant responses via FKBP-mediated protection of mitochondrial integrity". 1362:

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

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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-κB 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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Due to the lack of synthesis of ATP in the mitochondria under hypoxic stress or hypoxia, AMPK will also become active and thus inhibit mTORC1 through its processes.

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Akt will also phosphorylate PRAS40, causing it to fall off of the Raptor protein located on mTORC1. Since PRAS40 prevents Raptor from recruiting mTORC1's substrates

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De P, Miskimins K, Dey N, et al. (August 2013). "Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: old targets new hope".

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phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462. These phosphorylated sites will recruit the cytosolic anchoring protein

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promote longevity in humans. Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.

6849: 6248:"Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes" 6416:

Lv X, Ma X, Hu Y (August 2013). "Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment".

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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

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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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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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is also inhibited by rapamycin in some cell culture lines and tissues, particularly those that express high levels of FKBP12 and low levels of FKBP51.

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Zask A, Verheijen JC, Richard DJ (July 2011). "Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review".

5930:"Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature" 2762:"Osmotic stress regulates mammalian target of rapamycin (mTOR) complex 1 via c-Jun N-terminal Kinase (JNK)-mediated Raptor protein phosphorylation" 1183:

development. Treating stem cells with rapamycin will also slow their proliferation, conserving the stem cells in their undifferentiated condition.

227: 66: 3552:"mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events" 8394: 1072:

associates with active mTOR. Following membrane damage galectin-8 no longer interacts with mTOR but instead switches to complexes containing

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Saucedo LJ, Gao X, Chiarelli DA, et al. (June 2003). "Rheb promotes cell growth as a component of the insulin/TOR signalling network".

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heterodimers to switch to their active conformation. Active Rag heterodimers interact with raptor, localizing mTORC1 to the surface of late

8436: 7597: 6900: 1492: 2607:"Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance" 8545: 3149:"Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis" 1663:"GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR" 928:. Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the 7283: 7170: 888:, which prevent premature translation of proteins. Once the initiation complex is assembled at the 5' cap of mRNA, it will recruit the 439:

Almost all of the variables required for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 protein complex.

5516:"Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle" 4814:"Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth" 1754:

Fang Y, Vilella-Bach M, Bachmann R, et al. (November 2001). "Phosphatidic acid-mediated mitogenic activation of mTOR signaling".

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adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation to begin.

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group and is in its inactive GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein

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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

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Fabrizio P, Pozza F, Pletcher SD, et al. (April 2001). "Regulation of longevity and stress resistance by Sch9 in yeast".

71: 9018: 8284: 7259: 6537: 9013: 8540: 5072:"Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development" 2507:"The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1" 1258:

in skeletal muscle cells that result in mTOR phosphorylation, the activation of mTORC1, and subsequently the initiation of

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scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.

7074: 403: 251: 90: 5832:"Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system" 4922:"Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling" 2656:"Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis" 970:). PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex. 8272: 1319:, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of 8597: 1221:

of rapamycin inhibiting the immune system response has been linked to several reasons, including its interaction with

1172:. mTORC1 activity plays a critical role in the growth and proliferation of stem cells. Knocking out mTORC1 results in 8712: 7529: 7519: 7204: 2853: 6834: 3700:

Pullen N, Dennis PB, Andjelkovic M, et al. (January 1998). "Phosphorylation and activation of p70s6k by PDK1".

410:. Recently it has been also demonstrated that cellular bicarbonate metabolism can be regulated by mTORC1 signaling. 8211: 3601:"Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site" 1205:

during the expansion phase of T cell development . This inhibition also allows for an increase in quality of these

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eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B (

1044:, Atg17, and Atg101. This prevents the structure from being recruited to the preautophagosomal structure at the 797:

that can activate AMPK. More studies on this aspect of mTORC1 may help shed light on its strong link to cancer.

9033: 2350:"A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1" 1396: 4269:"Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease" 1064:

and is inhibited when lysosomal membrane is damaged through a protein complex termed GALTOR. GALTOR contains

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elevation in the blood, its signaling ensures that there is energy for protein synthesis to take place. In a

362: 51: 24: 3357:"Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway" 7083: 1614:"mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery" 1410: 1033: 775: 951:

has been spliced out. Once S6K binds to this complex, increased translation on these mRNA regions occurs.

770:, need to be present. If these levels of ATP are not present, due to its hydrolysis into other forms like 244: 5694:"Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins" 5559:, et al. (February 2007). "Targeting mammalian target of rapamycin (mTOR) for health and diseases". 4636:

Apel K, Hirt H (2004). "Reactive oxygen species: metabolism, oxidative stress, and signal transduction".

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There have been several dietary compounds that have been suggested to inhibit mTORC1 signaling including

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has been degraded by the eIF4A helicase. Once the ribosome reaches the AUG codon, translation can begin.

746: 603:, its removal will allow the two substrates to be recruited to mTORC1 and thereby activated in this way. 83: 3259:"Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex" 3006:

Hardie DG (October 2007). "AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy".

2813:"JNK signaling promotes intestinal tumorigenesis through activation of mTOR complex 1 in Apc(Δ716) mice" 9023: 8983: 8107: 7925: 7421: 6726:"Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters" 6338:

Schenone S, Brullo C, Musumeci F, et al. (2011). "ATP-competitive inhibitors of mTOR: an update".

1807:"Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance" 881: 778:

will become activated. AMPK will go on to inhibit energy consuming pathways such as protein synthesis.

3892:"Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase" 3515:

Lee T, Pelletier J (January 2012). "Eukaryotic initiation factor 4F: a vulnerability of tumor cells".

2705:"Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation" 1395:

complex. mTORC1 inhibition by everolimus has been shown to normalize tumor blood vessels, to increase

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response elements as well as antioxidants in response to increased levels of reactive oxygen species.

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Rag activity is regulated by at least two highly conserved complexes: the "GATOR1" complex containing

8969: 8956: 8943: 8930: 8917: 8904: 8891: 8853: 8097: 8092: 8087: 8077: 8072: 8067: 8057: 7852: 7627: 7223: 3802:"SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs" 1135: 580: 542: 448: 8863: 8817: 8760: 8320: 8311: 8262: 7028: 6873: 6828: 6824: 5387:"Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide" 1459: 1292: 1285: 1187: 1127: 701: 576: 131: 9038: 8765: 8620: 8043: 3851:"Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase" 1108: 771: 5023:"mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells" 4190:"Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans)" 766:

In order for translation to take place, abundant sources of energy, particularly in the form of

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Smith SM (June 2012). "Targeting mTOR in mantle cell lymphoma: current and future directions".

4318:"Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks" 2957:"Context-Dependent Regulation of Autophagy by IKK-NF-κB Signaling: Impact on the Aging Process" 1455: 1418: 1400: 1100:

and starts a quality control program that removes damaged lysosomes, referred to as lysophagy,

767: 615: 456: 6517: 6461:"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity" 5637:"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity" 1858:"The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis" 8786: 8705: 7319: 4649: 1308: 1201:. mTORC1 inhibition with rapamycin improves the ability of naïve T cells to become precursor 1089: 990: 978:

mTOR was found to be related to aging in 2001 when the ortholog of S6K, SCH9, was deleted in

940: 484: 478: 297: 1524:(Rheb inhibitor NR1), which inhibit the interaction of mTORC1 with its endogenous activator 301: 8858: 7886: 6778: 6680: 6623: 6566: 6472: 5648: 5284: 4825: 4146: 4044: 3940: 3756: 3709: 3656: 3211: 2716: 2410:

Ma XM, Blenis J (May 2009). "Molecular mechanisms of mTOR-mediated translational control".

2361: 2212: 1763: 1434: 1430: 1414: 1119: 731: 148: 136: 5438:"Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR" 321: 172: 8: 8822: 7995: 4284: 3984:"TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO" 3200:"Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis" 1529: 1429:. In 2007, mTORC1 inhibitors began being approved for treatments against cancers such as 1391:, everolimus is more selective for the mTORC1 protein complex, with little impact on the 1238: 1093: 678: 152: 6886: 6782: 6684: 6627: 6570: 6476: 5652: 5288: 4829: 4150: 4048: 3944: 3760: 3713: 3660: 3215: 2720: 2365: 2216: 1767: 9028: 8755: 8497: 8451: 6799: 6766: 6701: 6668: 6644: 6611: 6587: 6554: 6493: 6460: 6441: 6398: 6320: 6272: 6247: 6223: 6198: 6176: 6054: 6029: 6005: 5978: 5959: 5905: 5880: 5856: 5831: 5772: 5747: 5718: 5693: 5669: 5636: 5464: 5437: 5413: 5386: 5357: 5332: 5305: 5272: 5248: 5221: 5197: 5172: 5148: 5123: 4995: 4970: 4946: 4921: 4897: 4872: 4848: 4813: 4754: 4729: 4705: 4680: 4661: 4572: 4547: 4439: 4391: 4366: 4342: 4317: 4293: 4268: 4170: 4119: 4065: 4032: 4008: 3983: 3964: 3831: 3782: 3682: 3581: 3492: 3467: 3431:

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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There have been over 1,300 clinical trials conducted with mTOR inhibitors since 1970.

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Proud CG (November 2007). "Amino acids and mTOR signalling in anabolic function".

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S6K1 on at least two residues, with the most critical modification occurring on a

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through activation or inactivation of the TSC1/TSC2 complex, upstream of mTORC1.

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that functions as a nutrient/energy/redox sensor and controls protein synthesis.

355: 107: 5946: 5929: 5124:"mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells" 4613: 4596: 1197:, its inhibition of mTORC1 results in better quantity and quality of functional 924:

residue (T389). This event stimulates the subsequent phosphorylation of S6K1 by

331: 182: 8997: 8886: 8827: 6692: 6578: 6351: 6164: 6125: 6090: 5896: 5808: 5748:"Pushing the envelope in the mTOR pathway: the second generation of inhibitors" 5532: 5515: 4937: 4818:

Proceedings of the National Academy of Sciences of the United States of America

4745: 4033:"Rapamycin fed late in life extends lifespan in genetically heterogeneous mice" 3999: 3818: 3801: 3568: 3551: 3204:

Proceedings of the National Academy of Sciences of the United States of America

3051:"The AMPK signalling pathway coordinates cell growth, autophagy and metabolism" 2869: 2672: 2655: 2473: 1723: 1706: 1472:, which are not produced by structurally unrelated inhibitors of mTORC such as 1348: 1214: 1206: 1202: 1198: 1018: 6308: 6045: 5881:"Selective inhibition of mTORC1 in tumor vessels increases antitumor immunity" 5139: 4382: 2906:"Wnt signaling pathways in urological cancers: past decades and still growing" 2851: 2729: 2704: 2573: 1823: 864:). eIF4E is now free to join the eukaryotic translation initiation factor 4G ( 9007: 8791: 8750: 7232: 5238: 4986: 1426: 1375: 1150: 917: 836:

mTORC1 activates transcription and translation through its interactions with

7300: 6484: 6199:"Targeting the mTOR kinase domain: the second generation of mTOR inhibitors" 5660: 5454: 4838: 4790: 4158: 3952: 3308:"AMP-activated protein kinase, stress responses and cardiovascular diseases" 3224: 2778: 2622: 2373: 2224: 1775: 8740: 8171: 6996: 6808: 6751: 6710: 6653: 6596: 6502: 6437: 6394: 6359: 6316: 6281: 6232: 6172: 6133: 6112:

Fasolo A, Sessa C (2012). "Targeting mTOR pathways in human malignancies".

6098: 6063: 6014: 5955: 5914: 5865: 5816: 5781: 5727: 5678: 5621: 5580: 5500: 5473: 5422: 5366: 5314: 5257: 5206: 5157: 5105: 5056: 5004: 4955: 4906: 4857: 4798: 4763: 4714: 4657: 4622: 4581: 4525: 4516: 4499: 4484: 4475: 4458: 4435: 4400: 4351: 4302: 4253: 4215: 4166: 4115: 4074: 4017: 3960: 3917: 3908: 3891: 3876: 3867: 3850: 3827: 3626: 3617: 3600: 3577: 3536: 3501: 3452: 3417: 3382: 3341: 3292: 3243: 3184: 3133: 3084: 3027: 2992: 2941: 2922: 2887: 2838: 2797: 2738: 2681: 2640: 2591: 2542: 2523: 2491: 2431: 2391: 2334: 2277: 2242: 2185: 2136: 2079: 2030: 2012: 1981: 1940: 1891: 1842: 1783: 1732: 1688: 1639: 1591: 1384: 1112: 897: 5541: 4245: 3778: 3729: 3678: 2973: 2316: 1141:

Inhibition of mTORC1 has also been shown to increase transcription of the

1111:

can damage the DNA and proteins in cells. A majority of them arise in the

8964: 8899: 8735: 8377: 8009: 7949: 7832: 7752: 7476: 6669:"A small molecule inhibitor of Rheb selectively targets mTORC1 signaling" 6263: 4333: 4206: 4189: 3981: 2118: 1972: 1955: 1473: 1336: 1180: 967: 932:) and eIF4B, causing them to be recruited to the pre-initiation complex. 893: 860:, thereby releasing it from eukaryotic translation initiation factor 4E ( 722: 557: 461: 390: 280: 119: 6790: 6635: 6518:"Role of mTOR signaling in tumor cell motility, invasion and metastasis" 5995: 5296: 4056: 3483: 3373: 3356: 3274: 2301:"Spatial regulation of the mTORC1 system in amino acids sensing pathway" 2201:"The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1" 1582: 1565: 8465: 6939: 5847: 5709: 5188: 4696: 4427: 3528: 3323: 1380: 1165: 1131: 1069: 1065: 1014: 828: 666: 662: 650: 622:

and inhibit its sensitivity to insulin. This has great significance in

607: 275: 114: 3982:

Robida-Stubbs S, Glover-Cutter K, Lamming DW, et al. (May 2012).

880:). The helicase is required to remove hairpin loops that arise in the 872:). This complex then binds to the 5' cap of mRNA and will recruit the 606:

Furthermore, since insulin is a factor that is secreted by pancreatic

8938: 8912: 7426: 5556: 4500:"Autophagy and signaling: their role in cell survival and cell death" 2852:

Monaghan D, O'Connell E, Cruickshank FL, et al. (January 2014).

1521: 1406: 1388: 1359: 1259: 1176: 1097: 1022: 1006: 921: 749:(TNF-alpha) can induce mTOR activity through IKK beta, also known as 742: 382: 5596:"Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB" 4888: 3165: 3066: 3019: 2954: 2423: 2348:

Bar-Peled L, Chantranupong L, Cherniack AD, et al. (May 2013).

2061: 1021:

or proteins and smaller cellular debris via microautophagy from the

892:

small ribosomal subunit that is now capable of scanning for the AUG

813:) will stabilize and activate transcription of REDD1, also known as 8992: 7782: 7677: 7672: 7667: 6148: 5830:

Arriola Apelo SI, Neuman JC, Baar EL, et al. (February 2016).

4728:

Bonawitz ND, Chatenay-Lapointe M, Pan Y, et al. (April 2007).

2605:

McCubrey JA, Steelman LS, Chappell WH, et al. (October 2012).

2347: 2269: 1363: 1344: 1340: 1316: 1288: 1061: 995: 929: 873: 654: 497: 493: 427: 369:(commonly known as raptor), mammalian lethal with SEC13 protein 8 ( 7142:

3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring) kinase

6612:"Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40" 4873:"NRF2 and cancer: the good, the bad and the importance of context" 4727: 3147:

Nagalingam A, Arbiser JL, Bonner MY, et al. (February 2012).

2703:

Carrière A, Cargnello M, Julien LA, et al. (September 2008).

856:

Activated mTORC1 will phosphorylate translation repressor protein

8441: 8419: 8414: 8404: 8399: 8201: 8196: 8191: 8186: 8181: 8166: 8161: 7812: 7777: 7016: 7011: 7006: 6555:"A novel rapamycin analog is highly selective for mTORC1 in vivo" 3355:

Martelli AM, Evangelisti C, Chappell W, et al. (July 2011).

3354: 3198:

Horak P, Crawford AR, Vadysirisack DD, et al. (March 2010).

2458:"The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation" 1533: 1477: 1437:. mTORC1 inhibitors have recently been approved for treatment of 1409:, which is the drug name for rapamycin, was approved by the U.S. 1304: 1242: 1218: 1210: 1085: 1073: 638: 611: 394: 6552: 3100:"AMPK phosphorylation of raptor mediates a metabolic checkpoint" 1753: 1186:

mTORC1 plays a role in the differentiation and proliferation of

256: 95: 8951: 8721: 8671: 8666: 8661: 8656: 8651: 8646: 8641: 8592: 8587: 8582: 8577: 8572: 8555: 8550: 8424: 8409: 8360: 8355: 8340: 8335: 8330: 8325: 8299: 8294: 8289: 8277: 8255: 8250: 8142: 8117: 7792: 7617: 7612: 7607: 7602: 7587: 7431: 7368: 7363: 7358: 7334: 7160: 7155: 7129: 7124: 7119: 7109: 7104: 7094: 6934: 6865: 6553:

Schreiber KH, Arriola Apelo SI, Yu D, et al. (July 2019).

4594: 4316:

Alers S, Löffler AS, Wesselborg S, et al. (January 2012).

1481: 1469: 1464: 1392: 1368: 1266: 1173: 1142: 948: 857: 841: 689: 596: 588: 546: 510: 444: 378: 374: 263: 102: 5692:

Schreiber KH, Ortiz D, Academia EC, et al. (April 2015).

5070:

Gangloff YG, Mueller M, Dann SG, et al. (November 2004).

4136: 3468:"Control of mammalian translation by mRNA structure near caps" 2604: 2504: 1905:

Sharma A, Hoeffer CA, Takayasu Y, et al. (January 2010).

1029:

and damaged organelles that can lead to cellular dysfunction.

545:

for Rag subunits A/B) and GATOR2 activates Rags by inhibiting

8925: 8567: 8560: 8470: 8367: 8267: 8245: 8240: 8235: 8230: 8225: 8137: 8132: 8127: 8122: 8112: 8082: 8062: 7939: 7934: 7915: 7910: 7900: 7876: 7871: 7866: 7842: 7837: 7827: 7822: 7817: 7807: 7787: 7772: 7767: 7762: 7742: 7737: 7727: 7722: 7717: 7712: 7707: 7697: 7692: 7687: 7682: 7662: 7657: 7652: 7647: 7642: 7637: 7622: 7572: 7567: 7461: 7456: 7451: 7446: 7441: 7436: 7397: 7329: 7324: 7273: 7268: 7194: 7189: 7184: 7150: 6944: 6929: 6924: 6919: 6914: 6909: 6724:

Kang SA, O'Neill DJ, Machl AW, et al. (September 2019).

3699: 3466:

Babendure JR, Babendure JL, Ding JH, et al. (May 2006).

3257:

Brugarolas J, Lei K, Hurley RL, et al. (December 2004).

3197: 3146: 3098:

Gwinn DM, Shackelford DB, Egan DF, et al. (April 2008).

3097: 2654:

Ma L, Chen Z, Erdjument-Bromage H, et al. (April 2005).

2653: 1904: 1422: 1299:

as an essential downstream mechanism in the mediation of its

1296: 1274: 1270: 1169: 1168:

in the body has been shown to help prevent against premature

1081: 1077: 959: 944: 925: 877: 869: 865: 861: 845: 814: 810: 790: 727: 709: 704:) signaling is part of the mitogen-activated protein kinase ( 685: 526: 518: 514: 370: 366: 212: 197: 6764: 6667:

Mahoney SJ, Narayan S, Molz L, et al. (February 2018).

6246:

Veilleux A, Houde VP, Bellmann K, et al. (April 2010).

6245: 5594:

Sarbassov DD, Ali SM, Sengupta S, et al. (April 2006).

5021:

Murakami M, Ichisaka T, Maeda M, et al. (August 2004).

4595:

Hasegawa J, Maejima I, Iwamoto R, et al. (March 2015).

4546:

Jia J, Abudu YP, Claude-Taupin A, et al. (April 2018).

3930: 3433:

The International Journal of Biochemistry & Cell Biology

2198: 575:

Insulin-like growth factors can activate mTORC1 through the

8460: 8387: 8382: 8372: 8345: 8102: 8052: 8033: 8028: 8023: 8018: 7973: 7968: 7963: 7958: 7905: 7861: 7802: 7797: 7747: 7732: 7702: 7632: 7548: 7543: 7538: 7471: 7373: 7314: 7309: 7213: 7179: 7064: 7059: 7054: 7023: 6991: 6979: 6974: 6969: 6959: 6954: 6767:"mTOR is a key modulator of ageing and age-related disease" 6723: 6458: 5829: 5794: 5691: 5634: 5020: 4548:"Galectins Control mTOR in Response to Endomembrane Damage" 4315: 3745:"Translation control: connecting mitogens and the ribosome" 3598: 3465: 2505:

Oshiro N, Takahashi R, Yoshino K, et al. (July 2007).

1525: 1332: 1041: 1037: 885: 750: 658: 642: 600: 522: 452: 440: 8690: 6666: 6337: 5745: 5486: 5270: 5069: 4031:

Harrison DE, Strong R, Sharp ZD, et al. (July 2009).

3550:

Holz MK, Ballif BA, Gygi SP, et al. (November 2005).

3256: 2955:

Salminen A, Hyttinen JM, Kauppinen A, et al. (2012).

2702: 2199:

Sancak Y, Peterson TR, Shaul YD, et al. (June 2008).

1855: 943:). Exon junction complexes span the mRNA region where two 504: 8429: 6964: 6949: 6765:

Johnson SC, Rabinovitch PS, Kaeberlein M (January 2013).

6459:

Lamming DW, Ye L, Katajisto P, et al. (March 2012).

5635:

Lamming DW, Ye L, Katajisto P, et al. (March 2012).

5593: 5271:

Araki K, Turner AP, Shaffer VO, et al. (July 2009).

4030: 3800:

Ma XM, Yoon SO, Richardson CJ, et al. (April 2008).

1956:"The evolution of the TOR pathway and its role in cancer" 1425:

covering for widening arteries to prevent against future

889: 584: 8619: 5979:"Everolimus-eluting stents in interventional cardiology" 5976: 5879:

Wang S, Raybuck A, Shiuan E, et al. (August 2020).

1811:

Journal of the International Society of Sports Nutrition

1661:

Kim DH, Sarbassov DD, Ali SM, et al. (April 2003).

5333:"The role of mTOR in memory CD8 T-cell differentiation" 5222:"Akt and mTOR in B Cell Activation and Differentiation" 4545: 3599:

Saitoh M, Pullen N, Brennan P, et al. (May 2002).

1907:"Dysregulation of mTOR signaling in fragile X syndrome" 1704: 1612:

Kim DH, Sarbassov DD, Ali SM, et al. (July 2002).

868:) and the eukaryotic translation initiation factor 4A ( 774:, and the ratio of AMP to ATP molecules gets too high, 618:

on mTORC1 signaling, S6K1 is able to phosphorylate the

32: 6294: 3799: 3645:"The modular phosphorylation and activation of p70s6k" 1856:

Ali E, Liponska A, O'Hara B, et al. (June 2022).

1798: 1458:

from phosphorylated S6K, that can inhibit the insulin

1134:

in the cytosol for ATP production rather than through

451:). Its GAP activity interacts with a G protein called 8981: 5436:

Liu M, Wilk SA, Wang A, et al. (November 2010).

4459:"Age-related decline in chaperone-mediated autophagy" 4088:

Lynn MA, Eden G, Ryan FJ, et al. (August 2021).

2255: 1487:

Second generation inhibitors are able to bind to the

1291:

has been found to activate the mTORC1 pathway in the

6610:

Yang H, Jiang X, Li B, et al. (December 2017).

6372: 5878: 5513: 5330: 4087: 3549: 1705:

Wullschleger S, Loewith R, Hall MN (February 2006).

1660: 1122:

in the mitochondria by enhancing the translation of

958:

S6K also can phosphorylate programmed cell death 4 (

688:, which helps it overcome the inhibitory effects of 5746:Vilar E, Perez-Garcia J, Tabernero J (March 2011). 5122:Chen C, Liu Y, Liu Y, et al. (November 2009). 2858:

Biochemical and Biophysical Research Communications

2810: 2152:"Amino acids and mTORC1: from lysosomes to disease" 2149: 2095:"Amino acids and mTORC1: from lysosomes to disease" 2092: 1611: 939:

that can get recruited to exon junction complexes (

6079:Best Practice & Research. Clinical Haematology 6030:"mTOR inhibitors in advanced renal cell carcinoma" 5273:"mTOR regulates memory CD8 T-cell differentiation" 4968: 4920:Li C, Reif MM, Craige SM, et al. (May 2016). 4681:"How mitochondria produce reactive oxygen species" 1953: 3742: 3395: 2879:20.500.11820/ba05d42b-8452-4391-8c4a-c2850cb28b12 2760:Kwak D, Choi S, Jeong H, et al. (May 2012). 2759: 2150:Efeyan A, Zoncu R, Sabatini DM (September 2012). 2093:Efeyan A, Zoncu R, Sabatini DM (September 2012). 2043: 9005: 6027: 5514:Vézina C, Kudelski A, Sehgal SN (October 1975). 4919: 4913: 2903: 2405: 2403: 2401: 809:conditions, hypoxia inducible factor one alpha ( 6609: 6192: 6190: 5741: 5739: 5737: 5554: 5435: 5380: 5378: 5376: 5326: 5324: 5170: 5121: 5117: 5115: 5016: 5014: 4812:Sun Q, Chen X, Ma J, et al. (March 2011). 4231: 4227: 4225: 2899: 2897: 2455: 2451: 2449: 1126:that encodes for the complexes involved in the 6196: 5927: 3638: 3636: 1700: 1698: 1441:. In 2010 they were approved for treatment of 1433:. In 2008 they were approved for treatment of 8706: 6901:Non-specific serine/threonine protein kinases 6850: 6758: 6717: 6603: 6409: 6366: 6331: 6288: 6028:Voss MH, Molina AM, Motzer RJ (August 2011). 5977:Townsend JC, Rideout P, Steinberg DH (2012). 4811: 4497: 4266: 3883: 3848: 3842: 3793: 3592: 3508: 3430: 3424: 3389: 3348: 3048: 2558:"Mechanisms of insulin resistance in obesity" 2398: 2044:Jewell JL, Russell RC, Guan KL (March 2013). 1118:Deletion of the TOR1 gene in yeast increases 417: 6239: 6187: 6146: 6140: 6105: 6070: 6034:Hematology/Oncology Clinics of North America 6021: 5970: 5921: 5872: 5823: 5788: 5734: 5548: 5480: 5429: 5373: 5321: 5264: 5213: 5164: 5112: 5063: 5011: 4962: 4864: 4805: 4770: 4721: 4672: 4629: 4491: 4450: 4407: 4367:"Molecules and their functions in autophagy" 4358: 4309: 4260: 4222: 4187: 4181: 4130: 4024: 3975: 3924: 3642: 3514: 3299: 3250: 3191: 3140: 3091: 3042: 2999: 2948: 2904:Majid S, Saini S, Dahiya R (February 2012). 2894: 2696: 2647: 2598: 2549: 2498: 2446: 2292: 2249: 2192: 2143: 2037: 1988: 1563: 1493:phosphatidylinositol 3-kinase-related kinase 1013:and is essential for the removal of damaged 973: 565: 472: 464:. This control is usually performed through 6111: 5507: 5331:Araki K, Youngblood B, Ahmed R (May 2010). 5219: 5171:Russell RC, Fang C, Guan KL (August 2011). 4969:Ho AD, Wagner W, Mahlknecht U (July 2005). 4541: 4539: 4537: 4535: 3693: 3633: 3305: 2811:Fujishita T, Aoki M, Taketo MM (May 2011). 2298: 1947: 1695: 1559: 1557: 1555: 1228: 1138:in the inner membrane of the mitochondria. 1032:Upon activation, mTORC1 will phosphorylate 361:mTOR Complex 1 (mTORC1) is composed of the 8713: 8699: 7284:Goodpasture-antigen-binding protein kinase 6857: 6843: 6509: 4456: 4364: 3889: 1954:Beauchamp EM, Platanias LC (August 2013). 1607: 1605: 1603: 1601: 1448: 1265:(i.e., the production of proteins such as 1103: 1036:(Atg 13), preventing it from entering the 7997:Serine/threonine-specific protein kinases 7171:(isocitrate dehydrogenase (NADP+)) kinase 6888:Serine/threonine-specific protein kinases 6870:Serine/threonine-specific protein kinases 6827:at the U.S. National Library of Medicine 6798: 6741: 6700: 6643: 6586: 6515: 6492: 6271: 6222: 6197:Zhang YJ, Duan Y, Zheng XF (April 2011). 6053: 6004: 5994: 5945: 5904: 5855: 5771: 5717: 5668: 5611: 5531: 5463: 5453: 5412: 5402: 5356: 5304: 5247: 5237: 5196: 5147: 5095: 5046: 4994: 4945: 4896: 4870: 4847: 4837: 4776: 4753: 4704: 4612: 4571: 4515: 4474: 4390: 4341: 4292: 4205: 4105: 4064: 4007: 3907: 3866: 3817: 3768: 3736: 3668: 3616: 3567: 3491: 3372: 3331: 3282: 3233: 3223: 3174: 3164: 3123: 3074: 2982: 2972: 2931: 2921: 2877: 2828: 2787: 2777: 2728: 2671: 2630: 2581: 2532: 2522: 2481: 2456:Mendoza MC, Er EE, Blenis J (June 2011). 2381: 2324: 2232: 2175: 2126: 2069: 2020: 1994: 1971: 1930: 1881: 1832: 1822: 1722: 1678: 1629: 1581: 1506: 1354: 684:RSK has also been shown to phosphorylate 653:is tethered to the plasma membrane via a 352:mechanistic target of rapamycin complex 1 8532:Receptor protein serine/threonine kinase 4650:10.1146/annurev.arplant.55.031903.141701 4635: 4532: 4365:Pyo JO, Nah J, Jung YK (February 2012). 3743:Peterson RT, Schreiber SL (March 1998). 3049:Mihaylova MM, Shaw RJ (September 2011). 2409: 2046:"Amino acid signalling upstream of mTOR" 1707:"TOR signaling in growth and metabolism" 1552: 1540:are also selective inhibitors of mTORC1 827: 641:, such as insulin like growth factor 1 ( 556: 421: 8515:Low-density-lipoprotein receptor kinase 5928:Nashan B, Citterio F (September 2012). 1598: 823: 505:Regulation of the Ragulator-Rag complex 348:mammalian target of rapamycin complex 1 9006: 6415: 4678: 4498:Codogno P, Meijer AJ (November 2005). 3008:Nature Reviews. Molecular Cell Biology 3005: 2412:Nature Reviews. Molecular Cell Biology 2050:Nature Reviews. Molecular Cell Biology 1654: 8694: 8618: 7994: 7260:Fas-activated serine/threonine kinase 6885: 6838: 6375:Expert Opinion on Therapeutic Patents 6076: 5384: 4413: 4371:Experimental & Molecular Medicine 2961:International Journal of Cell Biology 962:), which marks it for degradation by 832:Receptor Tyrosine Kinases and mTORC1. 552: 521:and the ""GATOR2" complex containing 367:regulatory-associated protein of mTOR 8632: 8541:Bone morphogenetic protein receptors 6147:Budde K, Gaedeke J (February 2012). 4285:10.1146/annurev-pathol-020712-163918 4267:Murrow L, Debnath J (January 2013). 3306:Wang S, Song P, Zou MH (June 2012). 2305:Acta Biochimica et Biophysica Sinica 2299:Suzuki T, Inoki K (September 2011). 1997:"Regulation of TOR by small GTPases" 1804: 1387:. Compared with the parent compound 1252:beta-hydroxy beta-methylbutyric acid 1096:, mTOR inhibition in turn activates 1009:is the major degradation pathway in 756: 7075:Dephospho-(reductase kinase) kinase 6153:American Journal of Kidney Diseases 5983:Vascular Health and Risk Management 5442:The Journal of Biological Chemistry 4463:The Journal of Biological Chemistry 4457:Cuervo AM, Dice JF (October 2000). 4234:The New England Journal of Medicine 3896:The Journal of Biological Chemistry 3855:The Journal of Biological Chemistry 3849:Chiang GG, Abraham RT (July 2005). 3605:The Journal of Biological Chemistry 2766:The Journal of Biological Chemistry 2511:The Journal of Biological Chemistry 1995:Durán RV, Hall MN (February 2012). 1747: 1055: 633: 13: 7530:G-protein coupled receptor kinases 4779:Antioxidants & Redox Signaling 2555: 1564:Hay N, Sonenberg N (August 2004). 1040:kinase complex, which consists of 677:(MAPK). Erk can go on to activate 570: 434: 14: 9050: 7520:Beta adrenergic receptor kinase-2 7205:(tyrosine 3-monooxygenase) kinase 6818: 4188:Blagosklonny MV (February 2010). 1566:"Upstream and downstream of mTOR" 1528:, are also being developed. Some 1413:(FDA) in 1999 to prevent against 800: 8991: 8212:Mitogen-activated protein kinase 6660: 6546: 6524:. Vol. 3. pp. 207–44. 6452: 6418:Expert Opinion on Drug Discovery 5349:10.1111/j.0105-2896.2010.00898.x 5088:10.1128/MCB.24.21.9508-9516.2004 5039:10.1128/MCB.24.15.6710-6718.2004 4597:"Selective autophagy: lysophagy" 4416:Biochemical Society Transactions 3643:Pullen N, Thomas G (June 1997). 1421:. In 2003, it was approved as a 935:Active S6K can bind to the SKAR 761: 541:. GATOR1 inhibits Rags (it is a 31: 8598:Anti-Müllerian hormone receptor 8481:(acetyl-CoA carboxylase) kinase 8153:(RNA-polymerase)-subunit kinase 7515:Beta adrenergic receptor kinase 7506:Beta adrenergic receptor kinase 6522:Advances in Cancer Drug Targets 5685: 5628: 5587: 4871:Sporn MB, Liby KT (July 2012). 4588: 4081: 3890:Holz MK, Blenis J (July 2005). 3543: 3459: 2845: 2804: 2753: 2341: 2086: 846:eukaryotic initiation factor 4E 8221:Extracellular signal-regulated 6743:10.1016/j.chembiol.2019.05.009 6530:10.2174/9781681082332116030009 5404:10.12688/f1000research.14344.1 5076:Molecular and Cellular Biology 5027:Molecular and Cellular Biology 4638:Annual Review of Plant Biology 4504:Cell Death and Differentiation 4322:Molecular and Cellular Biology 2462:Trends in Biochemical Sciences 1923:10.1523/JNEUROSCI.3696-09.2010 1898: 1849: 1401:adoptive cell transfer therapy 1397:tumor-infiltrating lymphocytes 716: 695: 404:β-hydroxy β-methylbutyric acid 1: 8285:P38 mitogen-activated protein 7384:cGMP-dependent protein kinase 7345:cAMP-dependent protein kinase 7041:Pyruvate dehydrogenase kinase 6987:Ataxia telangiectasia mutated 6114:Current Pharmaceutical Design 5764:10.1158/1535-7163.MCT-10-0905 5752:Molecular Cancer Therapeutics 3770:10.1016/S0960-9822(98)70152-6 3670:10.1016/S0014-5793(97)00323-2 3445:10.1016/s1357-2725(98)00131-9 3410:10.1016/j.cellsig.2011.08.010 1680:10.1016/S1097-2765(03)00114-X 1631:10.1016/S0092-8674(02)00808-5 1546: 1374:Rapamycin itself is not very 1326: 1233: 1213:in old mice, enhancing their 1159: 734:for the developing organism. 393:and their derivatives (e.g., 9019:Genes on human chromosome 17 7084:AMP-activated protein kinase 6430:10.1517/17460441.2013.800479 6387:10.1517/13543776.2011.584871 6215:10.1016/j.drudis.2011.02.008 5613:10.1016/j.molcel.2006.03.029 5573:10.1016/j.drudis.2006.12.008 5220:Limon JJ, Fruman DA (2012). 4564:10.1016/j.molcel.2018.03.009 4107:10.1016/j.celrep.2021.109564 3722:10.1126/science.279.5351.707 3116:10.1016/j.molcel.2008.03.003 2830:10.1053/j.gastro.2011.02.007 2168:10.1016/j.molmed.2012.05.007 2156:Trends in Molecular Medicine 2111:10.1016/j.molmed.2012.05.007 2099:Trends in Molecular Medicine 1874:10.1016/j.molcel.2022.06.008 1411:Food and Drug Administration 1034:autophagy-related protein 13 1001: 737: 426:Activation of mTORC1 at the 7: 9014:Genes on human chromosome 1 8720: 7999:(EC 2.7.11.21-EC 2.7.11.30) 6520:. In Atta-ur-Rahman (ed.). 6340:Current Medicinal Chemistry 5947:10.1097/TP.0b013e3182551021 4614:10.1016/j.ymeth.2014.12.014 1911:The Journal of Neuroscience 1301:rapid-acting antidepressant 747:tumor necrosis factor alpha 561:The General mTORC1 Pathway. 406:), mechanical stimuli, and 385:, insulin, growth factors, 10: 9055: 7926:Elongation factor 2 kinase 6890:(EC 2.7.11.1-EC 2.7.11.20) 6693:10.1038/s41467-018-03035-z 6579:10.1038/s41467-019-11174-0 6352:10.2174/092986711796391651 6165:10.1053/j.ajkd.2011.10.013 6126:10.2174/138161212800626210 6091:10.1016/j.beha.2012.04.008 5897:10.1172/jci.insight.139237 5809:10.1016/j.ctrv.2012.12.002 5533:10.7164/antibiotics.28.721 5520:The Journal of Antibiotics 4938:10.1016/j.niox.2016.03.003 4746:10.1016/j.cmet.2007.02.009 4679:Murphy MP (January 2009). 4273:Annual Review of Pathology 4000:10.1016/j.cmet.2012.04.007 3819:10.1016/j.cell.2008.02.031 3569:10.1016/j.cell.2005.10.024 3517:Future Medicinal Chemistry 2870:10.1016/j.bbrc.2013.12.041 2673:10.1016/j.cell.2005.02.031 2474:10.1016/j.tibs.2011.03.006 1724:10.1016/j.cell.2006.01.016 1254:(HMB) are known to induce 1090:Ragulator) thus inhibiting 669:(MAPKKK), which activates 476: 418:Activation at the lysosome 8877: 8869:Michaelis–Menten kinetics 8841: 8810: 8779: 8728: 8628: 8614: 8530: 8513: 8496: 8479: 8450: 8321:MAP kinase kinase kinases 8310: 8210: 8151: 8042: 8008: 8004: 7990: 7948: 7924: 7885: 7853:Myosin light-chain kinase 7851: 7559:Ca2+/calmodulin-dependent 7557: 7528: 7504: 7485: 7406: 7382: 7343: 7299: 7282: 7258: 7224:Myosin-heavy-chain kinase 7222: 7203: 7169: 7140: 7073: 7039: 6899: 6895: 6881: 6309:10.1016/j.bcp.2020.113975 6046:10.1016/j.hoc.2011.04.008 5140:10.1126/scisignal.2000559 4383:10.3858/emm.2012.44.2.029 2730:10.1016/j.cub.2008.07.078 2574:10.1007/s11684-013-0262-6 1824:10.1186/s12970-016-0118-y 1520:and small molecules like 1136:oxidative phosphorylation 974:Role in disease and aging 851: 700:c-Jun N-terminal kinase ( 673:(MAPKK), which activates 581:Akt/PKB signaling pathway 566:Receptor tyrosine kinases 543:GTPase-activating protein 473:The Ragulator-Rag complex 327: 317: 312: 308: 291: 286: 274: 262: 250: 238: 226: 218: 208: 203: 196: 178: 168: 163: 159: 142: 130: 125: 113: 101: 89: 77: 65: 57: 47: 42: 30: 23: 8761:Diffusion-limited enzyme 8621:Dual-specificity kinases 6829:Medical Subject Headings 6516:Zhou H, Huang S (2016). 6297:Biochemical Pharmacology 5797:Cancer Treatment Reviews 5239:10.3389/fimmu.2012.00228 4987:10.1038/sj.embor.7400436 1293:medial prefrontal cortex 1286:NMDA receptor antagonist 1277:), thereby facilitating 1229:As a biomolecular target 1188:hematopoietic stem cells 1128:electron transport chain 1060:mTORC1 is positioned on 1048:, inhibiting autophagy. 896:start site, because the 577:receptor tyrosine kinase 483:mTORC1 interacts at the 8044:Cyclin-dependent kinase 6485:10.1126/science.1215135 6252:Molecular Endocrinology 5661:10.1126/science.1215135 5455:10.1074/jbc.M110.169284 5226:Frontiers in Immunology 4839:10.1073/pnas.1014769108 4791:10.1089/ars.2005.7.1140 4685:The Biochemical Journal 4159:10.1126/science.1115535 3953:10.1126/science.1059497 3263:Genes & Development 3225:10.1073/pnas.0907705107 2779:10.1074/jbc.M111.326538 2623:10.18632/oncotarget.659 2374:10.1126/science.1232044 2225:10.1126/science.1157535 1776:10.1126/science.1066015 1570:Genes & Development 1468:activated immunophilin 1449:Second generation drugs 1417:in patients undergoing 1109:Reactive oxygen species 1104:Reactive oxygen species 947:come together after an 882:5' untranslated regions 37:mTORC1 heteromer, Human 4877:Nature Reviews. Cancer 4517:10.1038/sj.cdd.4401751 4510:(Suppl 2): 1509–1518. 4476:10.1074/jbc.M002102200 3909:10.1074/jbc.M504045200 3868:10.1074/jbc.M501707200 3618:10.1074/jbc.M201745200 3153:Breast Cancer Research 2923:10.1186/1476-4598-11-7 2524:10.1074/jbc.M702636200 2013:10.1038/embor.2011.257 1507:Third generation drugs 1456:negative feedback loop 1419:kidney transplantation 1355:First generation drugs 903: 833: 616:negative feedback loop 562: 431: 9034:Tor signaling pathway 8854:Eadie–Hofstee diagram 8787:Allosteric regulation 6825:mTORC1+complex,+human 6730:Cell Chemical Biology 6673:Nature Communications 6559:Nature Communications 5337:Immunological Reviews 4246:10.1056/NEJMra1205406 2562:Frontiers of Medicine 1805:Bond P (March 2016). 991:insulin growth factor 831: 560: 485:Ragulator-Rag complex 479:Ragulator-Rag complex 425: 8864:Lineweaver–Burk plot 7887:Phosphorylase kinase 6736:(9): 1203–1213.e13. 6264:10.1210/me.2009-0328 6203:Drug Discovery Today 5561:Drug Discovery Today 4981:(Suppl 1): S35–S38. 4334:10.1128/MCB.06159-11 4207:10.4161/cc.9.4.10766 1973:10.1038/onc.2012.567 1435:mantle cell lymphoma 1431:renal cell carcinoma 1415:transplant rejection 1120:cellular respiration 824:Downstream signaling 789:LKB1, also known as 645:), can activate the 447:activating protein ( 6791:10.1038/nature11861 6783:2013Natur.493..338J 6685:2018NatCo...9..548M 6636:10.1038/nature25023 6628:2017Natur.552..368Y 6571:2019NatCo..10.3194S 6477:2012Sci...335.1638L 6471:(6076): 1638–1643. 5996:10.2147/VHRM.S23388 5653:2012Sci...335.1638L 5647:(6076): 1638–1643. 5489:Anticancer Research 5448:(47): 36387–36394. 5297:10.1038/nature08155 5289:2009Natur.460..108A 4830:2011PNAS..108.4129S 4785:(9–10): 1140–1149. 4469:(40): 31505–31513. 4422:(Pt 5): 1187–1190. 4151:2005Sci...310.1193K 4145:(5751): 1193–1196. 4057:10.1038/nature08221 4049:2009Natur.460..392H 3945:2001Sci...292..288F 3902:(28): 26089–26093. 3861:(27): 25485–25490. 3761:1998CBio....8.R248P 3714:1998Sci...279..707P 3661:1997FEBSL.410...78P 3611:(22): 20104–20112. 3484:10.1261/rna.2309906 3398:Cellular Signalling 3374:10.1038/leu.2011.46 3275:10.1101/gad.1256804 3216:2010PNAS..107.4675H 3055:Nature Cell Biology 2974:10.1155/2012/849541 2772:(22): 18398–18407. 2721:2008CBio...18.1269C 2556:Ye J (March 2013). 2517:(28): 20329–20339. 2366:2013Sci...340.1100B 2360:(6136): 1100–1106. 2317:10.1093/abbs/gmr066 2258:Nature Cell Biology 2217:2008Sci...320.1496S 2211:(5882): 1496–1501. 1868:(1): 3284–3298.e7. 1768:2001Sci...294.1942F 1762:(5548): 1942–1945. 1583:10.1101/gad.1212704 1532:inhibitors such as 1530:glucose transporter 1239:Resistance exercise 455:by hydrolyzing the 8823:Enzyme superfamily 8756:Enzyme promiscuity 8498:Tropomyosin kinase 8452:Tau-protein kinase 5848:10.1111/acel.12405 5710:10.1111/acel.12313 5189:10.1242/dev.058230 4697:10.1042/BJ20081386 4428:10.1042/BST0351187 3529:10.4155/fmc.11.150 3324:10.1042/CS20110625 1443:tuberous sclerosis 1279:muscle hypertrophy 1256:signaling cascades 1223:regulatory T cells 1027:protein aggregates 834: 628:insulin resistance 626:, which is due to 563: 553:Upstream signaling 432: 61:FRAP, FRAP2, FRAP1 9024:Protein complexes 8979: 8978: 8688: 8687: 8684: 8683: 8680: 8679: 8610: 8609: 8606: 8605: 7986: 7985: 7982: 7981: 7467:Protein kinase N1 7422:Protein kinase Cζ 6777:(7432): 338–345. 6622:(7685): 368–373. 6539:978-1-68108-233-2 6346:(20): 2995–3014. 6120:(19): 2766–2777. 5385:Duman RS (2018). 5283:(7251): 108–112. 5183:(16): 3343–3356. 5128:Science Signaling 5082:(21): 9508–9516. 5033:(15): 6710–6718. 4824:(10): 4129–4134. 4558:(1): 120–135.e8. 4043:(7253): 392–395. 3939:(5515): 288–290. 3708:(5351): 707–710. 3269:(23): 2893–2904. 3210:(10): 4675–4680. 2823:(5): 1556–63.e6. 2715:(17): 1269–1277. 2617:(10): 1068–1111. 1966:(34): 3923–3932. 1576:(16): 1926–1945. 1489:ATP-binding motif 1439:pancreatic cancer 1399:, and to improve 1263:protein synthesis 1241:, the amino acid 1195:immunosuppressant 1124:mitochondrial DNA 757:Energy and oxygen 732:protein synthesis 624:diabetes mellitus 387:phosphatidic acid 365:protein complex, 341: 340: 337: 336: 192: 191: 188: 187: 9046: 8996: 8995: 8987: 8859:Hanes–Woolf plot 8802:Enzyme activator 8797:Enzyme inhibitor 8771:Enzyme catalysis 8715: 8708: 8701: 8692: 8691: 8630: 8629: 8616: 8615: 8263:C-Jun N-terminal 8006: 8005: 7992: 7991: 7496:Rhodopsin kinase 7487:Rhodopsin kinase 7417:Protein kinase C 7408:Protein kinase C 7393:Protein kinase G 7354:Protein kinase A 6965:Protein kinase B 6897: 6896: 6883: 6882: 6859: 6852: 6845: 6836: 6835: 6813: 6812: 6802: 6762: 6756: 6755: 6745: 6721: 6715: 6714: 6704: 6664: 6658: 6657: 6647: 6607: 6601: 6600: 6590: 6550: 6544: 6543: 6513: 6507: 6506: 6496: 6456: 6450: 6449: 6413: 6407: 6406: 6370: 6364: 6363: 6335: 6329: 6328: 6292: 6286: 6285: 6275: 6243: 6237: 6236: 6226: 6209:(7–8): 325–331. 6194: 6185: 6184: 6144: 6138: 6137: 6109: 6103: 6102: 6074: 6068: 6067: 6057: 6025: 6019: 6018: 6008: 5998: 5974: 5968: 5967: 5949: 5925: 5919: 5918: 5908: 5876: 5870: 5869: 5859: 5827: 5821: 5820: 5792: 5786: 5785: 5775: 5743: 5732: 5731: 5721: 5689: 5683: 5682: 5672: 5632: 5626: 5625: 5615: 5591: 5585: 5584: 5567:(3–4): 112–124. 5555:Tsang CK, Qi H, 5552: 5546: 5545: 5535: 5511: 5505: 5504: 5495:(9): 3643–3649. 5484: 5478: 5477: 5467: 5457: 5433: 5427: 5426: 5416: 5406: 5382: 5371: 5370: 5360: 5328: 5319: 5318: 5308: 5268: 5262: 5261: 5251: 5241: 5217: 5211: 5210: 5200: 5168: 5162: 5161: 5151: 5119: 5110: 5109: 5099: 5067: 5061: 5060: 5050: 5018: 5009: 5008: 4998: 4966: 4960: 4959: 4949: 4917: 4911: 4910: 4900: 4868: 4862: 4861: 4851: 4841: 4809: 4803: 4802: 4774: 4768: 4767: 4757: 4725: 4719: 4718: 4708: 4676: 4670: 4669: 4633: 4627: 4626: 4616: 4592: 4586: 4585: 4575: 4543: 4530: 4529: 4519: 4495: 4489: 4488: 4478: 4454: 4448: 4447: 4411: 4405: 4404: 4394: 4362: 4356: 4355: 4345: 4313: 4307: 4306: 4296: 4264: 4258: 4257: 4229: 4220: 4219: 4209: 4185: 4179: 4178: 4134: 4128: 4127: 4109: 4085: 4079: 4078: 4068: 4028: 4022: 4021: 4011: 3979: 3973: 3972: 3928: 3922: 3921: 3911: 3887: 3881: 3880: 3870: 3846: 3840: 3839: 3821: 3797: 3791: 3790: 3772: 3755:(7): R248–R250. 3740: 3734: 3733: 3697: 3691: 3690: 3672: 3640: 3631: 3630: 3620: 3596: 3590: 3589: 3571: 3547: 3541: 3540: 3512: 3506: 3505: 3495: 3463: 3457: 3456: 3428: 3422: 3421: 3393: 3387: 3386: 3376: 3367:(7): 1064–1079. 3352: 3346: 3345: 3335: 3312:Clinical Science 3303: 3297: 3296: 3286: 3254: 3248: 3247: 3237: 3227: 3195: 3189: 3188: 3178: 3168: 3144: 3138: 3137: 3127: 3095: 3089: 3088: 3078: 3061:(9): 1016–1023. 3046: 3040: 3039: 3003: 2997: 2996: 2986: 2976: 2952: 2946: 2945: 2935: 2925: 2910:Molecular Cancer 2901: 2892: 2891: 2881: 2849: 2843: 2842: 2832: 2817:Gastroenterology 2808: 2802: 2801: 2791: 2781: 2757: 2751: 2750: 2732: 2700: 2694: 2693: 2675: 2651: 2645: 2644: 2634: 2602: 2596: 2595: 2585: 2553: 2547: 2546: 2536: 2526: 2502: 2496: 2495: 2485: 2453: 2444: 2443: 2407: 2396: 2395: 2385: 2345: 2339: 2338: 2328: 2296: 2290: 2289: 2253: 2247: 2246: 2236: 2196: 2190: 2189: 2179: 2147: 2141: 2140: 2130: 2090: 2084: 2083: 2073: 2041: 2035: 2034: 2024: 1992: 1986: 1985: 1975: 1951: 1945: 1944: 1934: 1902: 1896: 1895: 1885: 1853: 1847: 1846: 1836: 1826: 1802: 1796: 1795: 1751: 1745: 1744: 1726: 1702: 1693: 1692: 1682: 1658: 1652: 1651: 1633: 1609: 1596: 1595: 1585: 1561: 1247: 1246: 1164:Conservation of 1088:(a component of 1056:Lysosomal damage 1011:eukaryotic cells 964:ubiquitin ligase 937:scaffold protein 795:tumor suppressor 647:MAPK/ERK pathway 634:MAPK/ERK pathway 620:insulin receptor 408:oxidative stress 399: 398: 346:, also known as 310: 309: 194: 193: 161: 160: 35: 21: 20: 9054: 9053: 9049: 9048: 9047: 9045: 9044: 9043: 9004: 9003: 9002: 8990: 8982: 8980: 8975: 8887:Oxidoreductases 8873: 8849:Enzyme kinetics 8837: 8833:List of enzymes 8806: 8775: 8746:Catalytic triad 8724: 8719: 8689: 8676: 8624: 8602: 8526: 8509: 8492: 8475: 8446: 8306: 8206: 8177:P70-S6 Kinase 1 8147: 8038: 8000: 7978: 7944: 7920: 7881: 7847: 7553: 7524: 7500: 7481: 7402: 7378: 7339: 7295: 7278: 7254: 7248:Aurora C kinase 7243:Aurora B kinase 7238:Aurora A kinase 7218: 7199: 7165: 7136: 7069: 7035: 6891: 6877: 6863: 6821: 6816: 6763: 6759: 6722: 6718: 6665: 6661: 6608: 6604: 6551: 6547: 6540: 6514: 6510: 6457: 6453: 6424:(8): 991–1012. 6414: 6410: 6371: 6367: 6336: 6332: 6293: 6289: 6244: 6240: 6195: 6188: 6145: 6141: 6110: 6106: 6075: 6071: 6026: 6022: 5975: 5971: 5934:Transplantation 5926: 5922: 5891:(15): e139237. 5877: 5873: 5828: 5824: 5793: 5789: 5744: 5735: 5690: 5686: 5633: 5629: 5592: 5588: 5553: 5549: 5526:(10): 721–726. 5512: 5508: 5485: 5481: 5434: 5430: 5383: 5374: 5329: 5322: 5269: 5265: 5218: 5214: 5169: 5165: 5120: 5113: 5068: 5064: 5019: 5012: 4967: 4963: 4918: 4914: 4889:10.1038/nrc3278 4869: 4865: 4810: 4806: 4775: 4771: 4734:Cell Metabolism 4726: 4722: 4677: 4673: 4634: 4630: 4593: 4589: 4544: 4533: 4496: 4492: 4455: 4451: 4412: 4408: 4363: 4359: 4314: 4310: 4265: 4261: 4230: 4223: 4186: 4182: 4135: 4131: 4086: 4082: 4029: 4025: 3988:Cell Metabolism 3980: 3976: 3929: 3925: 3888: 3884: 3847: 3843: 3798: 3794: 3749:Current Biology 3741: 3737: 3698: 3694: 3641: 3634: 3597: 3593: 3548: 3544: 3513: 3509: 3464: 3460: 3429: 3425: 3394: 3390: 3353: 3349: 3318:(12): 555–573. 3304: 3300: 3255: 3251: 3196: 3192: 3166:10.1186/bcr3128 3145: 3141: 3096: 3092: 3067:10.1038/ncb2329 3047: 3043: 3020:10.1038/nrm2249 3014:(10): 774–785. 3004: 3000: 2953: 2949: 2902: 2895: 2850: 2846: 2809: 2805: 2758: 2754: 2709:Current Biology 2701: 2697: 2652: 2648: 2603: 2599: 2554: 2550: 2503: 2499: 2454: 2447: 2424:10.1038/nrm2672 2408: 2399: 2346: 2342: 2297: 2293: 2254: 2250: 2197: 2193: 2148: 2144: 2091: 2087: 2062:10.1038/nrm3522 2042: 2038: 1993: 1989: 1952: 1948: 1903: 1899: 1854: 1850: 1803: 1799: 1752: 1748: 1703: 1696: 1659: 1655: 1610: 1599: 1562: 1553: 1549: 1509: 1501:clinical trials 1451: 1357: 1329: 1244: 1243: 1236: 1231: 1179:due to lack of 1162: 1106: 1058: 1046:plasma membrane 1004: 976: 906: 854: 838:p70-S6 Kinase 1 826: 803: 764: 759: 740: 719: 698: 661:binds with its 636: 573: 571:Akt/PKB pathway 568: 555: 507: 481: 475: 466:phosphorylation 437: 435:The TSC complex 420: 396: 395: 356:protein complex 38: 17: 16:Protein complex 12: 11: 5: 9052: 9042: 9041: 9039:Human proteins 9036: 9031: 9026: 9021: 9016: 9001: 9000: 8977: 8976: 8974: 8973: 8960: 8947: 8934: 8921: 8908: 8895: 8881: 8879: 8875: 8874: 8872: 8871: 8866: 8861: 8856: 8851: 8845: 8843: 8839: 8838: 8836: 8835: 8830: 8825: 8820: 8814: 8812: 8811:Classification 8808: 8807: 8805: 8804: 8799: 8794: 8789: 8783: 8781: 8777: 8776: 8774: 8773: 8768: 8763: 8758: 8753: 8748: 8743: 8738: 8732: 8730: 8726: 8725: 8718: 8717: 8710: 8703: 8695: 8686: 8685: 8682: 8681: 8678: 8677: 8675: 8674: 8669: 8664: 8659: 8654: 8649: 8644: 8638: 8636: 8626: 8625: 8612: 8611: 8608: 8607: 8604: 8603: 8601: 8600: 8595: 8590: 8585: 8580: 8575: 8570: 8565: 8564: 8563: 8558: 8553: 8548: 8537: 8535: 8534:(EC 2.7.11.30) 8528: 8527: 8525: 8524: 8520: 8518: 8517:(EC 2.7.11.29) 8511: 8510: 8508: 8507: 8503: 8501: 8500:(EC 2.7.11.28) 8494: 8493: 8491: 8490: 8486: 8484: 8483:(EC 2.7.11.27) 8477: 8476: 8474: 8473: 8468: 8463: 8457: 8455: 8454:(EC 2.7.11.26) 8448: 8447: 8445: 8444: 8439: 8434: 8433: 8432: 8427: 8422: 8417: 8412: 8407: 8402: 8392: 8391: 8390: 8385: 8380: 8375: 8365: 8364: 8363: 8358: 8353: 8348: 8343: 8338: 8333: 8328: 8317: 8315: 8314:(EC 2.7.11.25) 8308: 8307: 8305: 8304: 8303: 8302: 8297: 8292: 8282: 8281: 8280: 8275: 8270: 8260: 8259: 8258: 8253: 8248: 8243: 8238: 8233: 8228: 8217: 8215: 8214:(EC 2.7.11.24) 8208: 8207: 8205: 8204: 8199: 8194: 8189: 8184: 8179: 8174: 8169: 8164: 8158: 8156: 8155:(EC 2.7.11.23) 8149: 8148: 8146: 8145: 8140: 8135: 8130: 8125: 8120: 8115: 8110: 8105: 8100: 8095: 8090: 8085: 8080: 8075: 8070: 8065: 8060: 8055: 8049: 8047: 8046:(EC 2.7.11.22) 8040: 8039: 8037: 8036: 8031: 8026: 8021: 8015: 8013: 8012:(EC 2.7.11.21) 8002: 8001: 7988: 7987: 7984: 7983: 7980: 7979: 7977: 7976: 7971: 7966: 7961: 7955: 7953: 7952:(EC 2.7.11.21) 7946: 7945: 7943: 7942: 7937: 7931: 7929: 7928:(EC 2.7.11.20) 7922: 7921: 7919: 7918: 7913: 7908: 7903: 7898: 7892: 7890: 7889:(EC 2.7.11.19) 7883: 7882: 7880: 7879: 7874: 7869: 7864: 7858: 7856: 7855:(EC 2.7.11.18) 7849: 7848: 7846: 7845: 7840: 7835: 7830: 7825: 7820: 7815: 7810: 7805: 7800: 7795: 7790: 7785: 7780: 7775: 7770: 7765: 7760: 7755: 7750: 7745: 7740: 7735: 7730: 7725: 7720: 7715: 7710: 7705: 7700: 7695: 7690: 7685: 7680: 7675: 7670: 7665: 7660: 7655: 7650: 7645: 7640: 7635: 7630: 7625: 7620: 7615: 7610: 7605: 7600: 7595: 7590: 7585: 7580: 7575: 7570: 7564: 7562: 7561:(EC 2.7.11.17) 7555: 7554: 7552: 7551: 7546: 7541: 7535: 7533: 7532:(EC 2.7.11.16) 7526: 7525: 7523: 7522: 7517: 7511: 7509: 7508:(EC 2.7.11.15) 7502: 7501: 7499: 7498: 7492: 7490: 7489:(EC 2.7.11.14) 7483: 7482: 7480: 7479: 7474: 7469: 7464: 7459: 7454: 7449: 7444: 7439: 7434: 7429: 7424: 7419: 7413: 7411: 7410:(EC 2.7.11.13) 7404: 7403: 7401: 7400: 7395: 7389: 7387: 7386:(EC 2.7.11.12) 7380: 7379: 7377: 7376: 7371: 7366: 7361: 7356: 7350: 7348: 7347:(EC 2.7.11.11) 7341: 7340: 7338: 7337: 7332: 7327: 7322: 7317: 7312: 7306: 7304: 7303:(EC 2.7.11.10) 7297: 7296: 7294: 7293: 7289: 7287: 7280: 7279: 7277: 7276: 7271: 7265: 7263: 7256: 7255: 7253: 7252: 7251: 7250: 7245: 7240: 7229: 7227: 7220: 7219: 7217: 7216: 7210: 7208: 7201: 7200: 7198: 7197: 7192: 7187: 7182: 7176: 7174: 7167: 7166: 7164: 7163: 7158: 7153: 7147: 7145: 7138: 7137: 7135: 7134: 7133: 7132: 7127: 7122: 7114: 7113: 7112: 7107: 7099: 7098: 7097: 7092: 7080: 7078: 7071: 7070: 7068: 7067: 7062: 7057: 7052: 7046: 7044: 7037: 7036: 7034: 7033: 7032: 7031: 7021: 7020: 7019: 7014: 7009: 7004: 6994: 6989: 6984: 6983: 6982: 6977: 6972: 6962: 6957: 6952: 6947: 6942: 6937: 6932: 6927: 6922: 6917: 6912: 6906: 6904: 6893: 6892: 6879: 6878: 6862: 6861: 6854: 6847: 6839: 6833: 6832: 6820: 6819:External links 6817: 6815: 6814: 6757: 6716: 6659: 6602: 6545: 6538: 6508: 6451: 6408: 6381:(7): 1109–27. 6365: 6330: 6287: 6258:(4): 766–778. 6238: 6186: 6159:(2): 276–283. 6139: 6104: 6085:(2): 175–183. 6069: 6040:(4): 835–852. 6020: 5969: 5940:(6): 547–561. 5920: 5871: 5822: 5803:(5): 403–412. 5787: 5758:(3): 395–403. 5733: 5704:(2): 265–273. 5684: 5627: 5606:(2): 159–168. 5600:Molecular Cell 5586: 5547: 5506: 5479: 5428: 5372: 5343:(1): 234–243. 5320: 5263: 5212: 5163: 5111: 5062: 5010: 4961: 4912: 4883:(8): 564–571. 4863: 4804: 4769: 4740:(4): 265–277. 4720: 4671: 4628: 4587: 4552:Molecular Cell 4531: 4490: 4449: 4406: 4357: 4308: 4259: 4240:(7): 651–662. 4221: 4200:(4): 683–688. 4180: 4129: 4080: 4023: 3994:(5): 713–724. 3974: 3923: 3882: 3841: 3812:(2): 303–313. 3792: 3735: 3692: 3632: 3591: 3562:(4): 569–580. 3542: 3507: 3478:(5): 851–861. 3458: 3423: 3388: 3347: 3298: 3249: 3190: 3139: 3110:(2): 214–226. 3104:Molecular Cell 3090: 3041: 2998: 2947: 2893: 2864:(2): 761–767. 2844: 2803: 2752: 2695: 2666:(2): 179–193. 2646: 2597: 2548: 2497: 2468:(6): 320–328. 2445: 2418:(5): 307–318. 2397: 2340: 2311:(9): 671–679. 2291: 2270:10.1038/ncb996 2264:(6): 566–571. 2248: 2191: 2162:(9): 524–533. 2142: 2105:(9): 524–533. 2085: 2056:(3): 133–139. 2036: 2007:(2): 121–128. 1987: 1946: 1917:(2): 694–702. 1897: 1862:Molecular Cell 1848: 1797: 1746: 1717:(3): 471–484. 1694: 1673:(4): 895–904. 1667:Molecular Cell 1653: 1624:(2): 163–175. 1597: 1550: 1548: 1545: 1508: 1505: 1450: 1447: 1356: 1353: 1328: 1325: 1295:(mPFC) of the 1235: 1232: 1230: 1227: 1215:immune systems 1207:memory T cells 1203:memory T cells 1199:memory T cells 1161: 1158: 1105: 1102: 1057: 1054: 1019:macroautophagy 1003: 1000: 975: 972: 918:phosphorylates 905: 902: 853: 850: 825: 822: 802: 801:Hypoxic stress 799: 763: 760: 758: 755: 739: 736: 718: 715: 697: 694: 635: 632: 583:. Ultimately, 572: 569: 567: 564: 554: 551: 506: 503: 477:Main article: 474: 471: 436: 433: 419: 416: 339: 338: 335: 334: 329: 325: 324: 319: 315: 314: 306: 305: 295: 289: 288: 284: 283: 278: 272: 271: 269:NM_001163034.1 266: 260: 259: 254: 248: 247: 242: 236: 235: 230: 224: 223: 220: 216: 215: 210: 206: 205: 201: 200: 190: 189: 186: 185: 180: 176: 175: 170: 166: 165: 157: 156: 146: 140: 139: 134: 128: 127: 123: 122: 117: 111: 110: 105: 99: 98: 93: 87: 86: 81: 75: 74: 69: 63: 62: 59: 55: 54: 49: 45: 44: 40: 39: 36: 28: 27: 15: 9: 6: 4: 3: 2: 9051: 9040: 9037: 9035: 9032: 9030: 9027: 9025: 9022: 9020: 9017: 9015: 9012: 9011: 9009: 8999: 8994: 8989: 8988: 8985: 8971: 8967: 8966: 8961: 8958: 8954: 8953: 8948: 8945: 8941: 8940: 8935: 8932: 8928: 8927: 8922: 8919: 8915: 8914: 8909: 8906: 8902: 8901: 8896: 8893: 8889: 8888: 8883: 8882: 8880: 8876: 8870: 8867: 8865: 8862: 8860: 8857: 8855: 8852: 8850: 8847: 8846: 8844: 8840: 8834: 8831: 8829: 8828:Enzyme family 8826: 8824: 8821: 8819: 8816: 8815: 8813: 8809: 8803: 8800: 8798: 8795: 8793: 8792:Cooperativity 8790: 8788: 8785: 8784: 8782: 8778: 8772: 8769: 8767: 8764: 8762: 8759: 8757: 8754: 8752: 8751:Oxyanion hole 8749: 8747: 8744: 8742: 8739: 8737: 8734: 8733: 8731: 8727: 8723: 8716: 8711: 8709: 8704: 8702: 8697: 8696: 8693: 8673: 8670: 8668: 8665: 8663: 8660: 8658: 8655: 8653: 8650: 8648: 8645: 8643: 8640: 8639: 8637: 8635: 8631: 8627: 8622: 8617: 8613: 8599: 8596: 8594: 8591: 8589: 8586: 8584: 8581: 8579: 8576: 8574: 8571: 8569: 8566: 8562: 8559: 8557: 8554: 8552: 8549: 8547: 8544: 8543: 8542: 8539: 8538: 8536: 8533: 8529: 8522: 8521: 8519: 8516: 8512: 8505: 8504: 8502: 8499: 8495: 8488: 8487: 8485: 8482: 8478: 8472: 8469: 8467: 8464: 8462: 8459: 8458: 8456: 8453: 8449: 8443: 8440: 8438: 8435: 8431: 8428: 8426: 8423: 8421: 8418: 8416: 8413: 8411: 8408: 8406: 8403: 8401: 8398: 8397: 8396: 8393: 8389: 8386: 8384: 8381: 8379: 8376: 8374: 8371: 8370: 8369: 8366: 8362: 8359: 8357: 8354: 8352: 8349: 8347: 8344: 8342: 8339: 8337: 8334: 8332: 8329: 8327: 8324: 8323: 8322: 8319: 8318: 8316: 8313: 8309: 8301: 8298: 8296: 8293: 8291: 8288: 8287: 8286: 8283: 8279: 8276: 8274: 8271: 8269: 8266: 8265: 8264: 8261: 8257: 8254: 8252: 8249: 8247: 8244: 8242: 8239: 8237: 8234: 8232: 8229: 8227: 8224: 8223: 8222: 8219: 8218: 8216: 8213: 8209: 8203: 8200: 8198: 8195: 8193: 8190: 8188: 8185: 8183: 8180: 8178: 8175: 8173: 8170: 8168: 8165: 8163: 8160: 8159: 8157: 8154: 8150: 8144: 8141: 8139: 8136: 8134: 8131: 8129: 8126: 8124: 8121: 8119: 8116: 8114: 8111: 8109: 8106: 8104: 8101: 8099: 8096: 8094: 8091: 8089: 8086: 8084: 8081: 8079: 8076: 8074: 8071: 8069: 8066: 8064: 8061: 8059: 8056: 8054: 8051: 8050: 8048: 8045: 8041: 8035: 8032: 8030: 8027: 8025: 8022: 8020: 8017: 8016: 8014: 8011: 8007: 8003: 7998: 7993: 7989: 7975: 7972: 7970: 7967: 7965: 7962: 7960: 7957: 7956: 7954: 7951: 7947: 7941: 7938: 7936: 7933: 7932: 7930: 7927: 7923: 7917: 7914: 7912: 7909: 7907: 7904: 7902: 7899: 7897: 7894: 7893: 7891: 7888: 7884: 7878: 7875: 7873: 7870: 7868: 7865: 7863: 7860: 7859: 7857: 7854: 7850: 7844: 7841: 7839: 7836: 7834: 7831: 7829: 7826: 7824: 7821: 7819: 7816: 7814: 7811: 7809: 7806: 7804: 7801: 7799: 7796: 7794: 7791: 7789: 7786: 7784: 7781: 7779: 7776: 7774: 7771: 7769: 7766: 7764: 7761: 7759: 7756: 7754: 7751: 7749: 7746: 7744: 7741: 7739: 7736: 7734: 7731: 7729: 7726: 7724: 7721: 7719: 7716: 7714: 7711: 7709: 7706: 7704: 7701: 7699: 7696: 7694: 7691: 7689: 7686: 7684: 7681: 7679: 7676: 7674: 7671: 7669: 7666: 7664: 7661: 7659: 7656: 7654: 7651: 7649: 7646: 7644: 7641: 7639: 7636: 7634: 7631: 7629: 7626: 7624: 7621: 7619: 7616: 7614: 7611: 7609: 7606: 7604: 7601: 7599: 7596: 7594: 7591: 7589: 7586: 7584: 7581: 7579: 7576: 7574: 7571: 7569: 7566: 7565: 7563: 7560: 7556: 7550: 7547: 7545: 7542: 7540: 7537: 7536: 7534: 7531: 7527: 7521: 7518: 7516: 7513: 7512: 7510: 7507: 7503: 7497: 7494: 7493: 7491: 7488: 7484: 7478: 7475: 7473: 7470: 7468: 7465: 7463: 7460: 7458: 7455: 7453: 7450: 7448: 7445: 7443: 7440: 7438: 7435: 7433: 7430: 7428: 7425: 7423: 7420: 7418: 7415: 7414: 7412: 7409: 7405: 7399: 7396: 7394: 7391: 7390: 7388: 7385: 7381: 7375: 7372: 7370: 7367: 7365: 7362: 7360: 7357: 7355: 7352: 7351: 7349: 7346: 7342: 7336: 7333: 7331: 7328: 7326: 7323: 7321: 7318: 7316: 7313: 7311: 7308: 7307: 7305: 7302: 7298: 7291: 7290: 7288: 7286:(EC 2.7.11.9) 7285: 7281: 7275: 7272: 7270: 7267: 7266: 7264: 7262:(EC 2.7.11.8) 7261: 7257: 7249: 7246: 7244: 7241: 7239: 7236: 7235: 7234: 7233:Aurora kinase 7231: 7230: 7228: 7226:(EC 2.7.11.7) 7225: 7221: 7215: 7212: 7211: 7209: 7207:(EC 2.7.11.6) 7206: 7202: 7196: 7193: 7191: 7188: 7186: 7183: 7181: 7178: 7177: 7175: 7173:(EC 2.7.11.5) 7172: 7168: 7162: 7159: 7157: 7154: 7152: 7149: 7148: 7146: 7144:(EC 2.7.11.4) 7143: 7139: 7131: 7128: 7126: 7123: 7121: 7118: 7117: 7115: 7111: 7108: 7106: 7103: 7102: 7100: 7096: 7093: 7091: 7088: 7087: 7085: 7082: 7081: 7079: 7077:(EC 2.7.11.3) 7076: 7072: 7066: 7063: 7061: 7058: 7056: 7053: 7051: 7048: 7047: 7045: 7043:(EC 2.7.11.2) 7042: 7038: 7030: 7027: 7026: 7025: 7022: 7018: 7015: 7013: 7010: 7008: 7005: 7003: 7000: 6999: 6998: 6997:EIF-2 kinases 6995: 6993: 6990: 6988: 6985: 6981: 6978: 6976: 6973: 6971: 6968: 6967: 6966: 6963: 6961: 6958: 6956: 6953: 6951: 6948: 6946: 6943: 6941: 6938: 6936: 6933: 6931: 6928: 6926: 6923: 6921: 6918: 6916: 6913: 6911: 6908: 6907: 6905: 6903:(EC 2.7.11.1) 6902: 6898: 6894: 6889: 6884: 6880: 6875: 6871: 6867: 6860: 6855: 6853: 6848: 6846: 6841: 6840: 6837: 6830: 6826: 6823: 6822: 6810: 6806: 6801: 6796: 6792: 6788: 6784: 6780: 6776: 6772: 6768: 6761: 6753: 6749: 6744: 6739: 6735: 6731: 6727: 6720: 6712: 6708: 6703: 6698: 6694: 6690: 6686: 6682: 6678: 6674: 6670: 6663: 6655: 6651: 6646: 6641: 6637: 6633: 6629: 6625: 6621: 6617: 6613: 6606: 6598: 6594: 6589: 6584: 6580: 6576: 6572: 6568: 6564: 6560: 6556: 6549: 6541: 6535: 6531: 6527: 6523: 6519: 6512: 6504: 6500: 6495: 6490: 6486: 6482: 6478: 6474: 6470: 6466: 6462: 6455: 6447: 6443: 6439: 6435: 6431: 6427: 6423: 6419: 6412: 6404: 6400: 6396: 6392: 6388: 6384: 6380: 6376: 6369: 6361: 6357: 6353: 6349: 6345: 6341: 6334: 6326: 6322: 6318: 6314: 6310: 6306: 6302: 6298: 6291: 6283: 6279: 6274: 6269: 6265: 6261: 6257: 6253: 6249: 6242: 6234: 6230: 6225: 6220: 6216: 6212: 6208: 6204: 6200: 6193: 6191: 6182: 6178: 6174: 6170: 6166: 6162: 6158: 6154: 6150: 6143: 6135: 6131: 6127: 6123: 6119: 6115: 6108: 6100: 6096: 6092: 6088: 6084: 6080: 6073: 6065: 6061: 6056: 6051: 6047: 6043: 6039: 6035: 6031: 6024: 6016: 6012: 6007: 6002: 5997: 5992: 5988: 5984: 5980: 5973: 5965: 5961: 5957: 5953: 5948: 5943: 5939: 5935: 5931: 5924: 5916: 5912: 5907: 5902: 5898: 5894: 5890: 5886: 5882: 5875: 5867: 5863: 5858: 5853: 5849: 5845: 5841: 5837: 5833: 5826: 5818: 5814: 5810: 5806: 5802: 5798: 5791: 5783: 5779: 5774: 5769: 5765: 5761: 5757: 5753: 5749: 5742: 5740: 5738: 5729: 5725: 5720: 5715: 5711: 5707: 5703: 5699: 5695: 5688: 5680: 5676: 5671: 5666: 5662: 5658: 5654: 5650: 5646: 5642: 5638: 5631: 5623: 5619: 5614: 5609: 5605: 5601: 5597: 5590: 5582: 5578: 5574: 5570: 5566: 5562: 5558: 5551: 5543: 5539: 5534: 5529: 5525: 5521: 5517: 5510: 5502: 5498: 5494: 5490: 5483: 5475: 5471: 5466: 5461: 5456: 5451: 5447: 5443: 5439: 5432: 5424: 5420: 5415: 5410: 5405: 5400: 5396: 5392: 5391:F1000Research 5388: 5381: 5379: 5377: 5368: 5364: 5359: 5354: 5350: 5346: 5342: 5338: 5334: 5327: 5325: 5316: 5312: 5307: 5302: 5298: 5294: 5290: 5286: 5282: 5278: 5274: 5267: 5259: 5255: 5250: 5245: 5240: 5235: 5231: 5227: 5223: 5216: 5208: 5204: 5199: 5194: 5190: 5186: 5182: 5178: 5174: 5167: 5159: 5155: 5150: 5145: 5141: 5137: 5133: 5129: 5125: 5118: 5116: 5107: 5103: 5098: 5093: 5089: 5085: 5081: 5077: 5073: 5066: 5058: 5054: 5049: 5044: 5040: 5036: 5032: 5028: 5024: 5017: 5015: 5006: 5002: 4997: 4992: 4988: 4984: 4980: 4976: 4972: 4965: 4957: 4953: 4948: 4943: 4939: 4935: 4931: 4927: 4923: 4916: 4908: 4904: 4899: 4894: 4890: 4886: 4882: 4878: 4874: 4867: 4859: 4855: 4850: 4845: 4840: 4835: 4831: 4827: 4823: 4819: 4815: 4808: 4800: 4796: 4792: 4788: 4784: 4780: 4773: 4765: 4761: 4756: 4751: 4747: 4743: 4739: 4735: 4731: 4724: 4716: 4712: 4707: 4702: 4698: 4694: 4690: 4686: 4682: 4675: 4667: 4663: 4659: 4655: 4651: 4647: 4643: 4639: 4632: 4624: 4620: 4615: 4610: 4606: 4602: 4598: 4591: 4583: 4579: 4574: 4569: 4565: 4561: 4557: 4553: 4549: 4542: 4540: 4538: 4536: 4527: 4523: 4518: 4513: 4509: 4505: 4501: 4494: 4486: 4482: 4477: 4472: 4468: 4464: 4460: 4453: 4445: 4441: 4437: 4433: 4429: 4425: 4421: 4417: 4410: 4402: 4398: 4393: 4388: 4384: 4380: 4376: 4372: 4368: 4361: 4353: 4349: 4344: 4339: 4335: 4331: 4327: 4323: 4319: 4312: 4304: 4300: 4295: 4290: 4286: 4282: 4278: 4274: 4270: 4263: 4255: 4251: 4247: 4243: 4239: 4235: 4228: 4226: 4217: 4213: 4208: 4203: 4199: 4195: 4191: 4184: 4176: 4172: 4168: 4164: 4160: 4156: 4152: 4148: 4144: 4140: 4133: 4125: 4121: 4117: 4113: 4108: 4103: 4100:(8): 109564. 4099: 4095: 4091: 4084: 4076: 4072: 4067: 4062: 4058: 4054: 4050: 4046: 4042: 4038: 4034: 4027: 4019: 4015: 4010: 4005: 4001: 3997: 3993: 3989: 3985: 3978: 3970: 3966: 3962: 3958: 3954: 3950: 3946: 3942: 3938: 3934: 3927: 3919: 3915: 3910: 3905: 3901: 3897: 3893: 3886: 3878: 3874: 3869: 3864: 3860: 3856: 3852: 3845: 3837: 3833: 3829: 3825: 3820: 3815: 3811: 3807: 3803: 3796: 3788: 3784: 3780: 3776: 3771: 3766: 3762: 3758: 3754: 3750: 3746: 3739: 3731: 3727: 3723: 3719: 3715: 3711: 3707: 3703: 3696: 3688: 3684: 3680: 3676: 3671: 3666: 3662: 3658: 3654: 3650: 3646: 3639: 3637: 3628: 3624: 3619: 3614: 3610: 3606: 3602: 3595: 3587: 3583: 3579: 3575: 3570: 3565: 3561: 3557: 3553: 3546: 3538: 3534: 3530: 3526: 3522: 3518: 3511: 3503: 3499: 3494: 3489: 3485: 3481: 3477: 3473: 3469: 3462: 3454: 3450: 3446: 3442: 3438: 3434: 3427: 3419: 3415: 3411: 3407: 3403: 3399: 3392: 3384: 3380: 3375: 3370: 3366: 3362: 3358: 3351: 3343: 3339: 3334: 3329: 3325: 3321: 3317: 3313: 3309: 3302: 3294: 3290: 3285: 3280: 3276: 3272: 3268: 3264: 3260: 3253: 3245: 3241: 3236: 3231: 3226: 3221: 3217: 3213: 3209: 3205: 3201: 3194: 3186: 3182: 3177: 3172: 3167: 3162: 3158: 3154: 3150: 3143: 3135: 3131: 3126: 3121: 3117: 3113: 3109: 3105: 3101: 3094: 3086: 3082: 3077: 3072: 3068: 3064: 3060: 3056: 3052: 3045: 3037: 3033: 3029: 3025: 3021: 3017: 3013: 3009: 3002: 2994: 2990: 2985: 2980: 2975: 2970: 2966: 2962: 2958: 2951: 2943: 2939: 2934: 2929: 2924: 2919: 2915: 2911: 2907: 2900: 2898: 2889: 2885: 2880: 2875: 2871: 2867: 2863: 2859: 2855: 2848: 2840: 2836: 2831: 2826: 2822: 2818: 2814: 2807: 2799: 2795: 2790: 2785: 2780: 2775: 2771: 2767: 2763: 2756: 2748: 2744: 2740: 2736: 2731: 2726: 2722: 2718: 2714: 2710: 2706: 2699: 2691: 2687: 2683: 2679: 2674: 2669: 2665: 2661: 2657: 2650: 2642: 2638: 2633: 2628: 2624: 2620: 2616: 2612: 2608: 2601: 2593: 2589: 2584: 2579: 2575: 2571: 2567: 2563: 2559: 2552: 2544: 2540: 2535: 2530: 2525: 2520: 2516: 2512: 2508: 2501: 2493: 2489: 2484: 2479: 2475: 2471: 2467: 2463: 2459: 2452: 2450: 2441: 2437: 2433: 2429: 2425: 2421: 2417: 2413: 2406: 2404: 2402: 2393: 2389: 2384: 2379: 2375: 2371: 2367: 2363: 2359: 2355: 2351: 2344: 2336: 2332: 2327: 2322: 2318: 2314: 2310: 2306: 2302: 2295: 2287: 2283: 2279: 2275: 2271: 2267: 2263: 2259: 2252: 2244: 2240: 2235: 2230: 2226: 2222: 2218: 2214: 2210: 2206: 2202: 2195: 2187: 2183: 2178: 2173: 2169: 2165: 2161: 2157: 2153: 2146: 2138: 2134: 2129: 2124: 2120: 2119:1721.1/106904 2116: 2112: 2108: 2104: 2100: 2096: 2089: 2081: 2077: 2072: 2067: 2063: 2059: 2055: 2051: 2047: 2040: 2032: 2028: 2023: 2018: 2014: 2010: 2006: 2002: 1998: 1991: 1983: 1979: 1974: 1969: 1965: 1961: 1957: 1950: 1942: 1938: 1933: 1928: 1924: 1920: 1916: 1912: 1908: 1901: 1893: 1889: 1884: 1879: 1875: 1871: 1867: 1863: 1859: 1852: 1844: 1840: 1835: 1830: 1825: 1820: 1816: 1812: 1808: 1801: 1793: 1789: 1785: 1781: 1777: 1773: 1769: 1765: 1761: 1757: 1750: 1742: 1738: 1734: 1730: 1725: 1720: 1716: 1712: 1708: 1701: 1699: 1690: 1686: 1681: 1676: 1672: 1668: 1664: 1657: 1649: 1645: 1641: 1637: 1632: 1627: 1623: 1619: 1615: 1608: 1606: 1604: 1602: 1593: 1589: 1584: 1579: 1575: 1571: 1567: 1560: 1558: 1556: 1551: 1544: 1541: 1539: 1535: 1531: 1527: 1523: 1519: 1515: 1504: 1502: 1498: 1494: 1490: 1485: 1483: 1479: 1475: 1471: 1466: 1461: 1457: 1446: 1444: 1440: 1436: 1432: 1428: 1427:heart attacks 1424: 1420: 1416: 1412: 1408: 1404: 1402: 1398: 1394: 1390: 1386: 1382: 1377: 1376:water soluble 1372: 1370: 1365: 1361: 1352: 1350: 1346: 1342: 1338: 1334: 1324: 1322: 1318: 1314: 1310: 1306: 1302: 1298: 1294: 1290: 1287: 1282: 1280: 1276: 1272: 1268: 1264: 1261: 1257: 1253: 1249: 1240: 1226: 1224: 1220: 1216: 1212: 1208: 1204: 1200: 1196: 1191: 1189: 1184: 1182: 1178: 1175: 1171: 1167: 1157: 1154: 1152: 1151:electrophilic 1148: 1144: 1139: 1137: 1133: 1129: 1125: 1121: 1116: 1114: 1110: 1101: 1099: 1095: 1091: 1087: 1083: 1079: 1075: 1071: 1067: 1063: 1053: 1049: 1047: 1043: 1039: 1035: 1030: 1028: 1024: 1020: 1016: 1012: 1008: 999: 997: 992: 987: 985: 981: 980:S. cerevisiae 971: 969: 965: 961: 956: 952: 950: 946: 942: 938: 933: 931: 927: 923: 919: 914: 912: 901: 899: 895: 891: 887: 883: 879: 875: 871: 867: 863: 859: 849: 847: 843: 839: 830: 821: 818: 816: 812: 808: 798: 796: 793:, is a known 792: 787: 783: 779: 777: 773: 769: 762:Energy status 754: 752: 748: 744: 735: 733: 729: 724: 714: 711: 707: 703: 693: 691: 687: 682: 680: 676: 672: 668: 664: 660: 656: 652: 651:G protein Ras 648: 644: 640: 631: 629: 625: 621: 617: 613: 609: 604: 602: 598: 593: 590: 586: 582: 578: 559: 550: 548: 544: 540: 536: 532: 528: 524: 520: 516: 512: 502: 499: 495: 491: 486: 480: 470: 467: 463: 458: 454: 450: 446: 442: 429: 424: 415: 411: 409: 405: 401: 392: 388: 384: 380: 376: 372: 368: 364: 359: 357: 353: 349: 345: 333: 330: 326: 323: 320: 316: 311: 307: 304: 303: 299: 296: 294: 290: 285: 282: 279: 277: 273: 270: 267: 265: 261: 258: 255: 253: 249: 246: 243: 241: 237: 234: 231: 229: 225: 221: 217: 214: 211: 207: 202: 199: 195: 184: 181: 177: 174: 171: 167: 162: 158: 155: 154: 150: 147: 145: 141: 138: 135: 133: 129: 124: 121: 118: 116: 112: 109: 106: 104: 100: 97: 94: 92: 88: 85: 82: 80: 76: 73: 70: 68: 64: 60: 56: 53: 50: 46: 41: 34: 29: 26: 22: 19: 8965:Translocases 8962: 8949: 8936: 8923: 8910: 8900:Transferases 8897: 8884: 8741:Binding site 8172:P70S6 kinase 6774: 6770: 6760: 6733: 6729: 6719: 6676: 6672: 6662: 6619: 6615: 6605: 6562: 6558: 6548: 6521: 6511: 6468: 6464: 6454: 6421: 6417: 6411: 6378: 6374: 6368: 6343: 6339: 6333: 6300: 6296: 6290: 6255: 6251: 6241: 6206: 6202: 6156: 6152: 6142: 6117: 6113: 6107: 6082: 6078: 6072: 6037: 6033: 6023: 5986: 5982: 5972: 5937: 5933: 5923: 5888: 5884: 5874: 5842:(1): 28–38. 5839: 5835: 5825: 5800: 5796: 5790: 5755: 5751: 5701: 5697: 5687: 5644: 5640: 5630: 5603: 5599: 5589: 5564: 5560: 5550: 5523: 5519: 5509: 5492: 5488: 5482: 5445: 5441: 5431: 5394: 5390: 5340: 5336: 5280: 5276: 5266: 5229: 5225: 5215: 5180: 5176: 5166: 5134:(98): ra75. 5131: 5127: 5079: 5075: 5065: 5030: 5026: 4978: 4975:EMBO Reports 4974: 4964: 4929: 4926:Nitric Oxide 4925: 4915: 4880: 4876: 4866: 4821: 4817: 4807: 4782: 4778: 4772: 4737: 4733: 4723: 4688: 4684: 4674: 4641: 4637: 4631: 4604: 4600: 4590: 4555: 4551: 4507: 4503: 4493: 4466: 4462: 4452: 4419: 4415: 4409: 4377:(2): 73–80. 4374: 4370: 4360: 4325: 4321: 4311: 4276: 4272: 4262: 4237: 4233: 4197: 4193: 4183: 4142: 4138: 4132: 4097: 4094:Cell Reports 4093: 4083: 4040: 4036: 4026: 3991: 3987: 3977: 3936: 3932: 3926: 3899: 3895: 3885: 3858: 3854: 3844: 3809: 3805: 3795: 3752: 3748: 3738: 3705: 3701: 3695: 3655:(1): 78–82. 3652: 3649:FEBS Letters 3648: 3608: 3604: 3594: 3559: 3555: 3545: 3523:(1): 19–31. 3520: 3516: 3510: 3475: 3471: 3461: 3439:(1): 43–57. 3436: 3432: 3426: 3404:(1): 17–24. 3401: 3397: 3391: 3364: 3360: 3350: 3315: 3311: 3301: 3266: 3262: 3252: 3207: 3203: 3193: 3156: 3152: 3142: 3107: 3103: 3093: 3058: 3054: 3044: 3011: 3007: 3001: 2964: 2960: 2950: 2913: 2909: 2861: 2857: 2847: 2820: 2816: 2806: 2769: 2765: 2755: 2712: 2708: 2698: 2663: 2659: 2649: 2614: 2610: 2600: 2568:(1): 14–24. 2565: 2561: 2551: 2514: 2510: 2500: 2465: 2461: 2415: 2411: 2357: 2353: 2343: 2308: 2304: 2294: 2261: 2257: 2251: 2208: 2204: 2194: 2159: 2155: 2145: 2102: 2098: 2088: 2053: 2049: 2039: 2004: 2001:EMBO Reports 2000: 1990: 1963: 1959: 1949: 1914: 1910: 1900: 1865: 1861: 1851: 1814: 1810: 1800: 1759: 1755: 1749: 1714: 1710: 1670: 1666: 1656: 1621: 1617: 1573: 1569: 1542: 1510: 1486: 1452: 1405: 1385:temsirolimus 1373: 1358: 1330: 1283: 1260:myofibrillar 1237: 1192: 1185: 1163: 1155: 1146: 1140: 1117: 1113:mitochondria 1107: 1059: 1050: 1031: 1005: 988: 983: 979: 977: 957: 953: 934: 915: 907: 898:hairpin loop 855: 835: 819: 804: 788: 784: 780: 765: 741: 720: 699: 683: 637: 605: 594: 574: 508: 489: 482: 438: 412: 360: 351: 347: 343: 342: 300: 219:Alt. symbols 151: 58:Alt. symbols 18: 8736:Active site 8623:(EC 2.7.12) 8010:Polo kinase 7950:Polo kinase 6565:(1): 3194. 5989:: 393–404. 5885:JCI Insight 5177:Development 4691:(1): 1–13. 4644:: 373–399. 4607:: 128–132. 4328:(1): 2–11. 4279:: 105–137. 1474:gedatolisib 1337:resveratrol 1181:trophoblast 966:Beta-TrCP ( 894:start codon 840:(S6K1) and 723:Wnt pathway 717:Wnt pathway 696:JNK pathway 663:SH2 domains 462:heterodimer 391:amino acids 322:Swiss-model 204:Identifiers 173:Swiss-model 43:Identifiers 9008:Categories 8939:Isomerases 8913:Hydrolases 8780:Regulation 7301:IκB kinase 6876:2.7.11-12) 6679:(1): 548. 6303:: 113975. 5836:Aging Cell 5698:Aging Cell 4194:Cell Cycle 3159:(1): R35. 2967:: 849541. 2611:Oncotarget 1547:References 1381:everolimus 1327:Inhibitors 1321:depression 1234:Activators 1166:stem cells 1160:Stem cells 1132:glycolysis 1070:Galectin-8 1066:galectin-8 1015:organelles 984:C. elegans 608:beta cells 490:Rag GTPase 389:, certain 318:Structures 313:Search for 287:Other data 222:KOG1, Mip1 169:Structures 164:Search for 126:Other data 9029:EC 2.7.11 8818:EC number 7427:PKC alpha 6403:207474033 6325:215803320 4932:: 45–53. 4124:237306510 1522:HY-124798 1407:Sirolimus 1389:rapamycin 1360:Rapamycin 1313:modulator 1303:effects. 1177:lethality 1174:embryonic 1098:autophagy 1062:lysosomes 1023:cytoplasm 1007:Autophagy 1002:Autophagy 922:threonine 743:Cytokines 738:Cytokines 498:lysosomes 494:endosomes 383:rapamycin 228:NCBI gene 132:EC number 108:NM_004958 67:NCBI gene 8842:Kinetics 8766:Cofactor 8729:Activity 7783:KIAA0999 7678:MAPKAPK5 7673:MAPKAPK3 7668:MAPKAPK2 6809:23325216 6752:31231029 6711:29416044 6654:29236692 6597:31324799 6503:22461615 6446:22677288 6438:23668243 6395:21591993 6360:21651476 6317:32298692 6282:20203102 6233:21333749 6181:18525093 6173:22130643 6134:22475451 6099:22687453 6064:21763970 6015:22910420 5964:24753934 5956:22941182 5915:32759497 5866:26463117 5817:23352077 5782:21216931 5728:25652038 5679:22461615 5622:16603397 5581:17275731 5501:22993301 5474:20851890 5423:29899972 5367:20536567 5315:19543266 5258:22888331 5207:21791526 5158:19934433 5106:15485918 5057:15254238 5005:15995659 4956:26989010 4907:22810811 4858:21325052 4799:16115017 4764:17403371 4715:19061483 4666:17229119 4658:15377225 4623:25542097 4582:29625033 4526:16247498 4485:10806201 4444:13379878 4436:17956308 4401:22257882 4352:22025673 4303:23072311 4254:23406030 4216:20139716 4175:42188272 4167:16293764 4116:34433065 4075:19587680 4018:22560223 3969:44756177 3961:11292860 3918:15905173 3877:15899889 3836:13437701 3828:18423201 3687:36947968 3627:11914378 3586:11118504 3578:16286006 3537:22168162 3502:16540693 3453:10216943 3418:21906675 3383:21436840 3361:Leukemia 3342:22390198 3293:15545625 3244:20176937 3185:22353783 3134:18439900 3085:21892142 3036:38533515 3028:17712357 2993:22899934 2942:22325146 2888:24333448 2839:21320501 2798:22493283 2747:15088729 2739:18722121 2690:18663447 2682:15851026 2641:23085539 2592:23471659 2543:17517883 2492:21531565 2440:30790160 2432:19339977 2392:23723238 2335:21785113 2286:25954873 2278:12766776 2243:18497260 2186:22749019 2137:22749019 2080:23361334 2031:22240970 1982:23246968 1960:Oncogene 1941:20071534 1892:35772404 1843:26937223 1792:44444716 1784:11729323 1741:17195001 1733:16469695 1689:12718876 1640:12150925 1592:15314020 1497:phase II 1364:scaffold 1345:caffeine 1341:curcumin 1317:sestrin2 1289:ketamine 1248:-leucine 1217:. This 996:lysosome 930:ribosome 874:helicase 655:farnesyl 639:Mitogens 428:lysosome 400:-leucine 332:InterPro 183:InterPro 137:2.7.11.1 8998:Biology 8952:Ligases 8722:Enzymes 8442:MAP3K14 8420:MAP3K11 8415:MAP3K10 8405:MAP3K13 8400:MAP3K12 8202:RPS6KC1 8197:RPS6KA1 8192:RPS6KA3 8187:RPS6KA2 8182:RPS6KB2 8167:RPS6KA4 8162:RPS6KA5 7813:Kalirin 7778:SNF1LK2 7017:EIF2AK4 7012:EIF2AK3 6866:Kinases 6800:3687363 6779:Bibcode 6702:5803267 6681:Bibcode 6645:5750076 6624:Bibcode 6588:6642166 6567:Bibcode 6494:3324089 6473:Bibcode 6465:Science 6273:5417537 6224:3073023 6055:3587783 6006:3402052 5906:7455083 5857:4717280 5773:3413411 5719:4364838 5670:3324089 5649:Bibcode 5641:Science 5542:1102508 5465:2978567 5414:5968361 5397:: 659. 5358:3760155 5306:2710807 5285:Bibcode 5249:3412259 5232:: 228. 5198:3143559 5149:4020596 4996:1369281 4947:4860108 4898:3836441 4849:3054028 4826:Bibcode 4755:3460550 4706:2605959 4601:Methods 4573:5911935 4392:3296815 4343:3255710 4294:3971121 4147:Bibcode 4139:Science 4066:2786175 4045:Bibcode 4009:3348514 3941:Bibcode 3933:Science 3787:2528173 3779:9545190 3757:Bibcode 3730:9445476 3710:Bibcode 3702:Science 3679:9247127 3657:Bibcode 3493:1440912 3333:3367961 3235:2842042 3212:Bibcode 3176:3496153 3125:2674027 3076:3249400 2984:3412117 2933:3293036 2789:3365776 2717:Bibcode 2632:3717945 2583:3936017 2534:3199301 2483:3112285 2383:3728654 2362:Bibcode 2354:Science 2326:3160786 2234:2475333 2213:Bibcode 2205:Science 2177:3432651 2128:3432651 2071:3988467 2022:3271343 1932:3665010 1883:9444906 1834:4774173 1764:Bibcode 1756:Science 1648:4656930 1538:NV-6297 1534:NV-5440 1478:WYE-687 1349:alcohol 1305:NV-5138 1219:paradox 1211:B cells 1086:LAMTOR1 1074:SLC38A9 916:mTORC1 807:hypoxic 612:glucose 354:, is a 328:Domains 298:Chr. 17 276:UniProt 179:Domains 115:UniProt 8984:Portal 8926:Lyases 8672:MAP2K7 8667:MAP2K6 8662:MAP2K5 8657:MAP2K4 8652:MAP2K3 8647:MAP2K2 8642:MAP2K1 8593:ACVRL1 8588:ACVR2B 8583:ACVR2A 8578:ACVR1C 8573:ACVR1B 8556:BMPR1B 8551:BMPR1A 8425:MAP3K7 8410:MAP3K9 8361:MAP3K8 8356:MAP3K7 8351:MAP3K6 8346:MAP3K5 8341:MAP3K4 8336:MAP3K3 8331:MAP3K2 8326:MAP3K1 8300:MAPK14 8295:MAPK13 8290:MAPK11 8278:MAPK10 8256:MAPK15 8251:MAPK12 8143:CDC2L1 8118:CDC2L5 7793:SNF1LK 7618:CAMK2G 7613:CAMK2D 7608:CAMK2B 7603:CAMK2A 7593:CAMK1G 7588:CAMK1D 7583:CAMK1B 7578:CAMK1A 7432:PRKCB1 7369:PRKACA 7364:PRKACB 7359:PRKACG 7335:IKBKAP 7161:BCKDHB 7156:BCKDHA 7130:PRKAG3 7125:PRKAG2 7120:PRKAG1 7110:PRKAB2 7105:PRKAB1 7095:PRKAA2 7090:PRKAA1 6935:STK38L 6831:(MeSH) 6807: 6797: 6771:Nature 6750: 6709: 6699: 6652: 6642: 6616:Nature 6595: 6585: 6536: 6501: 6491: 6444: 6436: 6401: 6393: 6358: 6323: 6315: 6280: 6270: 6231: 6221: 6179: 6171: 6132: 6097: 6062: 6052: 6013: 6003: 5962: 5954: 5913: 5903: 5864: 5854: 5815: 5780: 5770: 5726: 5716: 5677: 5667: 5620: 5579: 5557:Liu LF 5540: 5499: 5472: 5462: 5421: 5411: 5365: 5355: 5313: 5303: 5277:Nature 5256: 5246: 5205: 5195: 5156: 5146: 5104: 5097:522282 5094: 5055: 5048:444840 5045: 5003: 4993: 4954: 4944: 4905: 4895: 4856: 4846: 4797: 4762: 4752: 4713: 4703: 4664: 4656: 4621: 4580: 4570: 4524: 4483: 4442: 4434: 4399: 4389: 4350: 4340: 4301: 4291: 4252: 4214: 4173: 4165: 4122: 4114: 4073: 4063: 4037:Nature 4016: 4006: 3967: 3959: 3916: 3875: 3834: 3826: 3785: 3777: 3728: 3685: 3677: 3625: 3584: 3576: 3535: 3500: 3490: 3451: 3416: 3381: 3340: 3330: 3291: 3284:534650 3281: 3242: 3232: 3183: 3173: 3132: 3122: 3083: 3073: 3034: 3026: 2991: 2981: 2940: 2930: 2886: 2837: 2796: 2786: 2745: 2737: 2688: 2680: 2639: 2629: 2590: 2580: 2541: 2531: 2490: 2480: 2438: 2430: 2390: 2380: 2333: 2323: 2284: 2276: 2241: 2231: 2184: 2174: 2135: 2125: 2078: 2068: 2029: 2019: 1980: 1939: 1929: 1890: 1880: 1841: 1831: 1790: 1782: 1739: 1731: 1687: 1646: 1638: 1590: 1518:PRAS40 1482:XL-388 1470:FKBP12 1465:mTORC2 1393:mTORC2 1369:mTORC2 1347:, and 1309:ligand 1273:, and 1267:myosin 1250:, and 1143:NFE2L2 1084:, and 949:intron 858:4E-BP1 852:4E-BP1 844:, the 842:4E-BP1 710:Raptor 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