mTOR - Knowledge

3930:(mTORC2) are: mTOR itself, mammalian lethal with sec13 protein 8 (mLST8; also known as GβL), and the inhibitory DEP domain containing mTOR-interacting protein (DEPTOR). Specific to mTORC1 is the regulator-associated protein of the mammalian target of rapamycin (Raptor) and proline-rich Akt substrate of 40 kDa (PRAS40)(Kim et al., 2002; Laplante and Sabatini, 2012). Raptor is essential to mTORC1 activity. The mTORC2 complex includes the rapamycin insensitive companion of mTOR (Rictor), mammalian stress activated MAP kinase-interacting protein 1 (mSIN1), and proteins observed with rictor 1 and 2 (PROTOR 1 and 2)(Jacinto et al., 2006; Jacinto et al., 2004; Pearce et al., 2007; Sarbassov et al., 2004)(Figure 1B). Rictor and mSIN1 are both critical to mTORC2 function. 2715:, which in turn activates mTOR. In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles. Chinese hamster ovary cells transfected with the 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma-secretase inhibitor. These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling. 376: 353: 2808: 2711:(AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression. In general, findings demonstrate mTOR signaling hyperactivity in AD brains. For example, postmortem studies of human AD brain reveal dysregulation in PTEN, Akt, S6K, and mTOR. mTOR signaling appears to be closely related to the presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively. In vitro studies have shown Aβ to be an activator of the 2727:

under-production via mTOR activity seem to contribute to impaired learning and memory. Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity. Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition.

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mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling. In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed. Cognitive impairments characteristic of AD appear to be mediated by the phosphorylation of PRAS-40, which detaches from and allows for the mTOR hyperactivity when it is phosphorylated; inhibiting PRAS-40 phosphorylation prevents Aβ-induced mTOR hyperactivity. Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD.

1925:, noting its original source and activity. Early testing revealed that rapamycin also had potent immunosuppressive and cytostatic anti-cancer activity. Rapamycin did not initially receive significant interest from the pharmaceutical industry until the 1980s, when Wyeth-Ayerst supported Sehgal's efforts to further investigate rapamycin's effect on the immune system. This eventually led to its FDA approval as an immunosuppressant following kidney transplantation. However, prior to its FDA approval, how rapamycin worked remained completely unknown. 275: 250: 13662: 13647: 13632: 13707: 13692: 13617: 2356:: Overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation. Constitutive deletion of Rictor in mice leads to embryonic lethality, while tissue specific deletion leads to a variety of phenotypes; a common phenotype of Rictor deletion in liver, white adipose tissue, and pancreatic beta cells is systemic glucose intolerance and insulin resistance in one or more tissues. Decreased Rictor expression in mice decreases male, but not female, lifespan. 627: 1989:, and to provide evidence that FKBP12–FK506 and FKBP12–rapamycin might act through gain-of-function mechanisms that target distinct cellular functions. These investigations included key studies by Francis Dumont and Nolan Sigal at Merck contributing to show that FK506 and rapamycin behave as reciprocal antagonists. These studies implicated FKBP12 as a possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade. 2660: 382: 281: 13677: 31: 2428: 15884: 2116: 2017:

protein in yeast that was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall. TOR was originally discovered at the Biozentrum and Sandoz Pharmaceuticals in 1991 in Basel, Switzerland, and the name TOR pays further homage to this discovery, as TOR means doorway or gate in German, and the city of Basel was once ringed by a wall punctuated with gates into the city, including the iconic

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mRNA and the growth of cells within the plant. However, the TORC1 complex activation stops catabolic processes such as autophagy from occurring. TOR kinase signaling in plants has been found to aid in senescence, flowering, root and leaf growth, embryogenesis, and the meristem activation above the root cap of a plant. mTOR is also found to be highly involved in developing embryo tissue in plants.

2021:. "mTOR" initially meant "mammalian target of rapamycin", but the meaning of the "m" was later changed to "mechanistic". Similarly, with subsequent discoveries the zebra fish TOR was named zTOR, the Arabidopsis thaliana TOR was named AtTOR, and the Drosophila TOR was named dTOR. In 2009 the FRAP1 gene name was officially changed by the 2061:. mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as 3927:

is not surprising then that mTOR signaling is implicated in the entire hierarchy of brain function including the proliferation of neural stem cells, the assembly and maintenance of circuits, experience-dependent plasticity and regulation of complex behaviors like feeding, sleep and circadian rhythms. ...

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The hyperphosphorylation of tau proteins into neurofibrillary tangles is one hallmark of AD. p70S6K activation has been shown to promote tangle formation as well as mTOR hyperactivity through increased phosphorylation and reduced dephosphorylation. It has also been proposed that mTOR contributes to

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in 1994; and by Candace J. Sabers, Mary M. Martin, Gregory J. Brunn, Josie M. Williams, Francis J. Dumont, Gregory Wiederrecht, and Robert T. Abraham in 1995. In 1991, working in yeast, Hall and colleagues identified the TOR1 and TOR2 genes. In 1993, Robert Cafferkey, George Livi, and colleagues, and

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The mTOR signaling pathway acts as a molecular systems integrator to support organismal and cellular interactions with the environment. The mTOR pathway regulates homeostasis by directly influencing protein synthesis, transcription, autophagy, metabolism, and organelle biogenesis and maintenance. It

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Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy; therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases,

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Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in the cortex and hippocampus of animal models of AD compared to controls. Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal

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Plants express the mechanistic target of rapamycin (mTOR) and have a TOR kinase complex. In plants, only the TORC1 complex is present unlike that of mammalian target of rapamycin which also contains the TORC2 complex. Plant species have TOR proteins in the protein kinase and FKBP-rapamycin binding

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was identified as the target of FKBP12-FK506. That of FKBP12-rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12-rapamycin in 1991 and 1993, followed by studies in 1994 when

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The TOR kinase complex has been known for having a role in the metabolism of plants. The TORC1 complex turns on when plants are living the proper environmental conditions to survive. Once activated, plant cells undergo particular anabolic reactions. These include plant development, translation of

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Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas. Reasons for constitutive activation are

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was used as its official gene symbol in humans. Because of these different names, mTOR, which had been first used by Robert T. Abraham, was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein and in homage to the original discovery of the TOR

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restriction, cause lifespan extension by decreasing mTOR activity. Some studies have suggested that mTOR signaling may increase during aging, at least in specific tissues like adipose tissue, and rapamycin may act in part by blocking this increase. An alternative theory is mTOR signaling is an

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mTOR function is mediated through two large biochemical complexes defined by their respective protein composition and have been extensively reviewed elsewhere(Dibble and Manning, 2013; Laplante and Sabatini, 2012)(Figure 1B). In brief, common to both mTOR complex 1 (mTORC1) and mTOR complex 2

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Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients. Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR. Both protein over- and

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The discovery of TOR and the subsequent identification of mTOR opened the door to the molecular and physiological study of what is now called the mTOR pathway and had a catalytic effect on the growth of the field of chemical biology, where small molecules are used as probes of biology.

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stimulates muscle protein synthesis (MPS) for a period of up to 48 hours following exercise (shown by dotted line). Ingestion of a protein-rich meal at any point during this period will augment the exercise-induced increase in muscle protein synthesis (shown by solid

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including AD. Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates. Perhaps the same treatment may be useful in clearing Aβ deposits as well.

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Rapamycin has a more complex effect on mTORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin.

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Toral-Barza L, Zhang WG, Lamison C, et al. (June 2005). "Characterization of the cloned full-length and a truncated human target of rapamycin: activity, specificity, and enzyme inhibition as studied by a high capacity assay".

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Völkl, Simon, et al. "Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome." Blood, The Journal of the American Society of Hematology 128.2 (2016): 227-238.

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subunit of two structurally distinct complexes: mTORC1 and mTORC2. The two complexes localize to different subcellular compartments, thus affecting their activation and function. Upon activation by Rheb, mTORC1 localizes to the

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Kougias DG, Nolan SO, Koss WA, et al. (April 2016). "Beta-hydroxy-beta-methylbutyrate ameliorates aging effects in the dendritic tree of pyramidal neurons in the medial prefrontal cortex of both male and female rats".

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Increasing mTOR activity was shown to drive cell cycle progression and increase cell proliferation mainly due to its effect on protein synthesis. Moreover, active mTOR supports tumor growth also indirectly by inhibiting

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Sekulić A, Hudson CC, Homme JL, et al. (July 2000). "A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells".

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Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS (glycogen synthase) can be increased in skeletal muscle. This discovery represents a potential novel therapeutic approach for

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on the lumenal side of the delimiting endomembrane. Following membrane damage, galectin-8, which normally associates with mTOR under homeostatic conditions, no longer interacts with mTOR but now instead binds to

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orthologue of mTORC1, is a regulator of both carbon and nitrogen metabolism; TOR1 KO strains regulate response to nitrogen as well as carbon availability, indicating that it is a key nutritional transducer in

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several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues. Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast

2476:, and while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. Calorie restriction and methionine restriction may act in part by limiting levels of 11843:

Takahashi T, Hara K, Inoue H, et al. (September 2000). "Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and in vitro".

2515:. These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates removal of dysfunctional cellular components via 3400:, have been reported to inhibit mTOR when applied to isolated cells in culture. As yet no high quality evidence exists that these substances inhibit mTOR signaling or extend lifespan when taken as 13250:"Stimulation of signal transducer and activator of transcription-1 (STAT1)-dependent gene transcription by lipopolysaccharide and interferon-gamma is regulated by mammalian target of rapamycin" 8817:"Coupling of mammalian target of rapamycin with phosphoinositide 3-kinase signaling pathway regulates protein phosphatase 2A- and glycogen synthase kinase-3 -dependent phosphorylation of Tau" 13661: 8198:

Li X, Alafuzoff I, Soininen H, et al. (August 2005). "Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain".

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Gómez-Linton DR, Alavez S, Alarcón-Aguilar A, et al. (October 2019). "Some naturally occurring compounds that increase longevity and stress resistance in model organisms of aging".

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Stephens L, Anderson K, Stokoe D, et al. (January 1998). "Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B".

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on serine residue Ser473, thus affecting metabolism and survival. Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by

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Chano T, Okabe H, Hulette CM (September 2007). "RB1CC1 insufficiency causes neuronal atrophy through mTOR signaling alteration and involved in the pathology of Alzheimer's diseases".

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is a negative regulator of autophagy in general, best studied during response to starvation, which is a metabolic response. During lysosomal damage however, mTOR inhibition activates

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Sabatini DM, Erdjument-Bromage H, Lui M, et al. (July 1994). "RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs".

2993:, membrane-permeant chemicals yielding osmotically active products (this type of injury can be modeled using membrane-permeant dipeptide precursors that polymerize in lysosomes), 10958: 13706: 13691: 10984: 4747:

Kunz J, Henriquez R, Schneider U, et al. (May 1993). "Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression".

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Kunz J, Henriquez R, Schneider U, et al. (May 1993). "Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression".

3183:, the enzymatic product of the class III PI3K Beclin 1-VPS34-ATG14. Thus, mTOR inactivation, initiated through GALTOR upon lysosomal damage, plus a simultaneous activation via 13186:

Edinger AL, Linardic CM, Chiang GG, et al. (December 2003). "Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells".

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or amino acid derivatives. Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during muscle wasting in old age,

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Jia K, Chen D, Riddle DL (August 2004). "The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span".

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El-Salem, Mouna, et al. "Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders." Laboratory Investigation 87.1 (2007): 29-39.

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Puighermanal E, Marsicano G, Busquets-Garcia A, et al. (September 2009). "Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling".

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Nemazanyy I, Espeillac C, Pende M, et al. (August 2013). "Role of PI3K, mTOR and Akt2 signalling in hepatic tumorigenesis via the control of PKM2 expression".

12342:"Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex" 13740: 8999:

Tischmeyer W, Schicknick H, Kraus M, et al. (August 2003). "Rapamycin-sensitive signalling in long-term consolidation of auditory cortex-dependent memory".

3214:); whereas ubiquitination by a glycoprotein-specific FBXO27-endowed ubiquitin ligase of several damage-exposed glycosylated lysosomal membrane proteins such as 2335:

The mTORC2 signaling pathway is less defined than the mTORC1 signaling pathway. The functions of the components of the mTORC complexes have been studied using

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Oshiro N, Yoshino K, Hidayat S, et al. (April 2004). "Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function".

11438:"Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase" 12434:

Kawai S, Enzan H, Hayashi Y, et al. (July 2003). "Vinculin: a novel marker for quiescent and activated hepatic stellate cells in human and rat livers".

3199:) of the autophagy systems listed above and further inactivates mTORC1, allows for strong autophagy induction and autophagic removal of damaged lysosomes. 13616: 12845:"The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses" 1969:

following organ transplantation. Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product

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Thomas GV, Tran C, Mellinghoff IK, et al. (January 2006). "Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer".

12479:"Two motifs in the translational repressor PHAS-I required for efficient phosphorylation by mammalian target of rapamycin and for recognition by raptor" 6892:

Kaeberlein M, Powers RW, Steffen KK, et al. (November 2005). "Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients".

6267:"Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1" 1530: 13733: 5005:

Beevers CS, Li F, Liu L, et al. (August 2006). "Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells".

3119:-driving components physically and functionally link up with each other integrating all processes necessary for autophagosomal formation: (i) the ULK1- 1511: 211: 12523:"The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif" 11997:

Choi J, Chen J, Schreiber SL, et al. (July 1996). "Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP".

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Jacinto E, Loewith R, Schmidt A, et al. (November 2004). "Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive".

2507:, the mTOR pathway is inhibited and ATP-consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the 13940: 4151:

Sehgal SN, Baker H, Vézina C (October 1975). "Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization".

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Harding MW, Galat A, Uehling DE, et al. (October 1989). "A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase".

4420:"Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin" 11950:"Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins" 5822:"Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology" 4287:"Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity" 3337:, and renal cell carcinoma (everolimus). The complete mechanism of these agents is not clear, but they are thought to function by impairing tumour 8437:

Zhang F, Beharry ZM, Harris TE, et al. (May 2009). "PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells".

12608:"Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation" 3016:. The process of mTOR inactivation following lysosomal/endomembrane is mediated by the protein complex termed GALTOR. At the heart of GALTOR is 15285: 12884:

Bernardi R, Guernah I, Jin D, et al. (August 2006). "PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR".

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Sabatini DM, Barrow RK, Blackshaw S, et al. (May 1999). "Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling".

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Liu J, Farmer JD, Lane WS, et al. (August 1991). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes".

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Magnuson B, Ekim B, Fingar DC (January 2012). "Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signaling networks".

3612: 3594: 15327: 14488: 13791: 13340:"Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR)" 2748: 1828: 11270:"Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy" 15436: 12050:"Kinetics of regulated protein-protein interactions revealed with firefly luciferase complementation imaging in cells and living animals" 11747:"Activation of mammalian target of rapamycin (mTOR) by insulin is associated with stimulation of 4EBP1 binding to dimeric mTOR complex 1" 5773:"Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton" 5567:"GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR" 4477:

Bierer BE, Somers PK, Wandless TJ, et al. (October 1990). "Probing immunosuppressant action with a nonnatural immunophilin ligand".

4005:"mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR" 2903: 3063:

response in its quality control function, leading to the process termed lysophagy that removes damaged lysosomes. At this stage another

2573:, an upstream effector of mTOR. Additionally, mTOR activity is deregulated in many cancers as a result of increased activity of PI3K or 14174: 14061: 12755:"Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation" 12226:

Ha SH, Kim DH, Kim IS, et al. (December 2006). "PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals".

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Sarbassov DD, Guertin DA, Ali SM, et al. (February 2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex".

2307:. This appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Suppression of 2005:

had identified in August 1991 and May 1993. Independently, George Livi and colleagues later reported the same genes, which they called

8579:"mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease" 5606:

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

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mTOR inhibitors may be useful for treating/preventing several age-associated conditions, including neurodegenerative diseases such as

1745: 14449: 9573:"Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease" 2523: 1738: 11221:"Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs" 9665:

Arenas, Daniel J., et al. "Increased mTOR activation in idiopathic multicentric Castleman disease." Blood 135.19 (2020): 1673-1684.

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inhibits age-related cognitive decline associated with dendritic pruning in animals, which is a phenomenon also observed in humans.

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Jimenez SA, Cronin PM, Koenig AS, et al. (15 February 2012). Varga J, Talavera F, Goldberg E, Mechaber AJ, Diamond HS (eds.).

3433: 3111:, many of them being under negative control of mTOR directly such as the ULK1-ATG13 complex, or indirectly, such as components of t 2178:. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is regulated by 12261:

Buerger C, DeVries B, Stambolic V (June 2006). "Localization of Rheb to the endomembrane is critical for its signaling function".

8390:"Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease" 3678:

Brown EJ, Albers MW, Shin TB, et al. (June 1994). "A mammalian protein targeted by G1-arresting rapamycin-receptor complex".

2613:. Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of 15524: 15405: 2740: 15111: 13980: 13213:

Leone M, Crowell KJ, Chen J, et al. (August 2006). "The FRB domain of mTOR: NMR solution structure and inhibitor design".

2586: 13676: 6557:"Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression" 15175: 14150: 13596: 8858:"Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling" 6408:"Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism" 3115:(Beclin 1, ATG14 and VPS34) since they depend on activating phosphorylations by ULK1 when it is not inhibited by mTOR. These 2278: 1883: 7102:"Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction" 3577: 2285:(InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR. 15904: 15431: 8528:"Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments" 2834: 54: 11415: 3234:, and TMEM192/transmembrane protein 192 may contribute to the execution of lysophagy via autophagic receptors such as p62/ 1954:, and colleagues independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes. 13965: 10394:"TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis" 8635:"Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism" 4191:

Heitman J, Movva NR, Hall MN (August 1991). "Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast".

3556: 2941: 2621:. mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of 2200: 1850:, which regulate different cellular processes. In particular, as a core component of both complexes, mTOR functions as a 10595:"The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14" 7259:"Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin" 15163: 13291:"Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR" 6798:"Carbon catabolite repression regulates amino acid permeases in Saccharomyces cerevisiae via the TOR signaling pathway" 3050: 2473: 15488: 4958:"Mammalian Target of Rapamycin: A Metabolic Rheostat for Regulating Adipose Tissue Function and Cardiovascular Health" 15603: 14420: 14410: 14095: 11092:

Bové J, Martínez-Vicente M, Vila M (August 2011). "Fighting neurodegeneration with rapamycin: mechanistic insights".

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Rosner M, Hanneder M, Siegel N, et al. (June 2008). "The mTOR pathway and its role in human genetic diseases".

7508:"The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity" 3269:

diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma.

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into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway in the

1911:), with the goal of identifying natural products from plants and soil with possible therapeutic potential. In 1972, 375: 15102: 12937:"Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site" 11410: 10644:"WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1" 4900: 3180: 2022: 13147:"Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site" 4677:

Fretz H, Albers MW, Galat A, et al. (February 1991). "Rapamycin and FK506 binding proteins (immunophilins)".

15929: 15371: 15043: 14405: 14396: 13670:: THE STRUCTURE OF THE IMMUNOPHILIN-IMMUNOSUPPRESSANT FKBP12-(C16)-ETHOXY RAPAMYCIN COMPLEX INTERACTING WITH HUMA 3581: 3560: 3223: 2796: 2650: 1851: 352: 12107:

Banaszynski LA, Liu CW, Wandless TJ (April 2005). "Characterization of the FKBP.rapamycin.FRB ternary complex".

8907:"Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway" 182:, FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS, mechanistic target of rapamycin, mechanistic target of rapamycin kinase 15919: 12301:"SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity" 9371:

Rubinsztein DC (October 2006). "The roles of intracellular protein-degradation pathways in neurodegeneration".

4579:"Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin" 2913: 2367:; inhibition of mTORC2 alone by PP242 prevents phosphorylation of Ser-473 site on AKT and arrests the cells in 2012:

The protein, now called mTOR, was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini;

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Groenewoud MJ, Zwartkruis FJ (August 2013). "Rheb and Rags come together at the lysosome to activate mTORC1".

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Faivre S, Kroemer G, Raymond E (August 2006). "Current development of mTOR inhibitors as anticancer agents".

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Tokunaga C, Yoshino K, Yonezawa K (January 2004). "mTOR integrates amino acid- and energy-sensing pathways".

9750: 7605:"MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation" 3404:

by humans, despite encouraging results in animals such as fruit flies and mice. Various trials are ongoing.

3369:, in elderly (65 and older), treated subjects had a reduced number of infections over the course of a year. 3202:

Additionally, several types of ubiquitination events parallel and complement the galectin-driven processes:

2989:

is inhibited when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading

1556: 15914: 13974: 12706:"Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity" 11507:"Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status" 6653:

Yang ZZ, Tschopp O, Baudry A, et al. (April 2004). "Physiological functions of protein kinase B/Akt".

5526:"mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery" 3164: 3120: 2883: 2504: 2492: 1961:

of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in

274: 249: 191: 13655:: THE STRUCTURE OF THE IMMUNOPHILIN-IMMUNOSUPPRESSANT FKBP12-RAPAMYCIN COMPLEX INTERACTING WITH HUMAN FRAP 13640:: THE STRUCTURE OF THE IMMUNOPHILIN-IMMUNOSUPPRESSANT FKBP12-RAPAMYCIN COMPLEX INTERACTING WITH HUMAN FRAP 9522:"Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability" 7151:"Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome" 2511:. Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits 11362:

Li W, Qin L, Feng R, et al. (July 2019). "Emerging senolytic agents derived from natural products".

7390:

Cota D, Proulx K, Smith KA, et al. (May 2006). "Hypothalamic mTOR signaling regulates food intake".

4892: 3413: 3254: 13060:"Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro" 10492:"Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy" 9801:"Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling" 2350:: Knockdown reduced mTORC2 activity that is indicated by decreased phosphorylation of mTORC2 substrates. 15874: 14998: 14816: 14312: 6025: 5659:"Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance" 4530:"The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells" 3206:

of TRIM16-ULK1-Beclin-1 stabilizes these complexes to promote autophagy activation as described above.

2955: 2594: 1917: 388: 287: 13019:"Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase" 2089:

complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.

15860: 15847: 15834: 15821: 15808: 15795: 15782: 15744: 14988: 14983: 14978: 14968: 14963: 14958: 14948: 14743: 14518: 14114: 13715:: ATOMIC STRUCTURES OF THE RAPAMYCIN ANALOGS IN COMPLEX WITH BOTH HUMAN FKBP12 AND FRB DOMAIN OF FRAP 13700:: ATOMIC STRUCTURES OF THE RAPAMYCIN ANALOGS IN COMPLEX WITH BOTH HUMAN FKBP12 AND FRB DOMAIN OF FRAP 13589: 5181:"The Plant Target of Rapamycin: A Conduc TOR of Nutrition and Metabolism in Photosynthetic Organisms" 3009: 2638: 2542:

for IL1A is highly dependent upon mTOR activity. mTOR activity increases levels of IL1A, mediated by

381: 280: 6308:"Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size" 178: 15754: 15708: 15651: 15211: 15202: 15153: 13919: 13764: 13528: 8727:"PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding" 7707: 3828:"Dual mTOR Inhibition Is Required to Prevent TGF-β-Mediated Fibrosis: Implications for Scleroderma" 3373: 3306: 2822: 2439: 2408: 1933:

The discovery of TOR and mTOR stemmed from independent studies of the natural product rapamycin by

1871: 1653: 1649: 199: 9699:"Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise" 3938: 3934: 15924: 15656: 15511: 14934: 12978:"Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase" 10258:"Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy" 2873: 2569:

gene. PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of

2551: 2496: 2452: 2274: 1875: 10931: 10546:"Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin" 9279:

McCray BA, Taylor JP (December 2008). "The role of autophagy in age-related neurodegeneration".

7446:"Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses" 5715:"mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s" 2148:

on the lysosome surface where it then becomes active in the presence of sufficient amino acids.

1721: 1700: 1674: 1645: 7656:"Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism" 3358: 3354: 3001: 2878: 2739:

Hyperactive mTOR pathways have been identified in certain lymphoproliferative diseases such as

2708: 2445: 10742:"Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy" 7705:

Wang R, Sunchu B, Perez VI (2017). "Rapamycin and the inhibition of the secretory phenotype".

7355:

Caron A, Richard D, Laplante M (Jul 2015). "The Roles of mTOR Complexes in Lipid Metabolism".

6128:"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity" 2807: 2480:

including leucine and methionine, which are potent activators of mTOR. The administration of

1973:(later called Tacrolimus) in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit 15677: 15596: 14210: 12804:"Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency" 9473:"Intracellular degradation of misfolded proteins in polyglutamine neurodegenerative diseases" 8482:"Evidence that production and release of amyloid beta-protein involves the endocytic pathway" 7756: 3156: 3112: 3088: 3046: 3005: 2712: 2320: 2145: 1921:, that he purified and initially reported to possess potent antifungal activity. He named it 13381:"mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state" 11176:

Estrela JM, Ortega A, Mena S, et al. (2013). "Pterostilbene: Biomedical applications".

15749: 14777: 13582: 13302: 12893: 12192: 12061: 12006: 11902: 11804: 11660: 11649:"TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function" 9861: 9380: 9194: 8164: 7457: 7399: 7162: 7056: 6999: 6901: 6701: 6226:"mTOR complex component Rictor interacts with PKCzeta and regulates cancer cell metastasis" 6139: 6078: 5934: 5883: 5784: 5726: 5615: 4635: 4486: 4431: 4200: 4104:"The origin story of rapamycin: systemic bias in biomedical research and cold war politics" 3687: 3326: 3293: 3250: 2908: 2671: 2602: 2477: 2018: 263: 6988:"Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway" 3325:. mTOR inhibitors have found use in the treatment of a variety of malignancies, including 219: 8: 15713: 14886: 9921: 7609: 7553: 3401: 3056: 2918: 2846: 2842: 2780: 2695:

mTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in

2531: 2464: 2403:), and growth deficiency (AKT1/AKT2). Mice heterozygous for AKT1 have increased lifespan. 2304: 2038: 13777: 13524: 13306: 12897: 12196: 12065: 12010: 11906: 11808: 11664: 9865: 9384: 9198: 8168: 7461: 7403: 7210:"Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice" 7166: 7060: 7003: 6905: 6705: 6506:"Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2" 6457:"Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan" 6143: 6100: 6073: 5938: 5887: 5788: 5730: 5619: 4639: 4490: 4435: 4204: 3691: 15909: 15646: 15388: 15342: 13500: 13475: 13405: 13380: 12917: 12730: 12705: 12632: 12607: 12459: 12416: 12030: 11974: 11949: 11868: 11621: 11596: 11572: 11547: 11387: 11344: 11296: 11269: 11245: 11220: 11201: 11117: 11033: 10907: 10880: 10815: 10790: 10766: 10741: 10717: 10692: 10668: 10643: 10619: 10594: 10570: 10545: 10516: 10491: 10467: 10442: 10418: 10393: 10282: 10257: 10230: 10205: 10178: 10151: 10042: 10017: 9980: 9955: 9933: 9884: 9849: 9825: 9800: 9781: 9723: 9698: 9548: 9521: 9497: 9472: 9448: 9423: 9404: 9348: 9323: 9304: 9215: 9182: 9158: 9133: 9068: 9043: 9024: 8981: 8933: 8906: 8882: 8857: 8792: 8767: 8661: 8634: 8608: 8554: 8527: 8462: 8414: 8389: 8362: 8337: 8310: 8286:"Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior" 8285: 8266: 8223: 8132: 8107: 8053: 8005: 7980: 7961: 7913: 7886: 7827: 7802: 7778: 7751: 7732: 7682: 7655: 7631: 7604: 7577: 7548: 7480: 7445: 7423: 7368: 7332: 7307: 7283: 7258: 7234: 7209: 7185: 7150: 7126: 7101: 7077: 7044: 7020: 6987: 6968: 6925: 6866: 6841: 6749:"Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae" 6724: 6689: 6581: 6556: 6532: 6505: 6481: 6456: 6432: 6407: 6383: 6356: 6332: 6307: 6160: 6127: 6049: 6020: 5996: 5969: 5907: 5848: 5821: 5685: 5658: 5639: 5490: 5465: 5446: 5398: 5373: 5308: 5283: 5259: 5234: 5207: 5180: 5074: 5049: 5030: 4982: 4957: 4869: 4842: 4818: 4791: 4772: 4729: 4659: 4608: 4559: 4510: 4362: 4267: 4224: 4128: 4103: 4084: 4029: 4004: 3912: 3887: 3852: 3827: 3761: 3711: 3013: 2997: 2990: 2922: 2760: 2598: 2382: 2359:

mTOR: Inhibition of mTORC1 and mTORC2 by PP242 pyrimidin-3-yl)-1H-indol-5-ol] leads to

2308: 2234: 1887: 1855: 223: 13446: 13429: 13315: 13290: 12779: 12754: 12084: 12049: 11719: 11702: 11673: 11648: 10856: 10839: 9488: 9109: 9092: 8498: 8481: 8405: 8108:"Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits" 7549:"Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research" 6773: 6748: 6630: 6605: 5583: 5566: 5542: 5525: 4311: 4286: 2221:

mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR (

1981:

signaling pathways, respectively. The two natural products were used to discover the

1445: 1440: 1435: 1430: 1425: 1420: 1415: 1410: 1405: 1400: 1395: 1390: 1385: 1380: 1375: 1370: 1365: 1360: 1355: 1350: 1345: 1340: 1335: 1330: 1325: 1320: 1315: 1310: 1305: 1300: 1295: 1290: 1285: 1280: 1275: 1270: 1265: 1260: 1255: 1250: 1245: 1240: 1235: 1230: 1225: 1220: 1215: 1210: 1205: 1200: 1195: 1190: 1185: 1180: 1175: 1170: 1165: 1160: 1155: 1150: 1145: 1140: 1135: 1130: 1125: 1120: 1115: 1110: 1105: 1100: 1095: 1090: 1085: 1080: 1075: 1070: 1065: 1060: 1055: 1050: 1045: 1040: 1035: 1030: 1025: 1020: 1015: 1010: 1005: 1000: 995: 990: 985: 980: 975: 970: 965: 960: 955: 950: 945: 940: 935: 930: 925: 920: 915: 910: 905: 900: 895: 890: 874: 869: 864: 859: 854: 849: 844: 839: 834: 829: 824: 819: 814: 809: 804: 799: 794: 789: 784: 779: 774: 769: 764: 759: 754: 738: 733: 728: 723: 718: 713: 708: 703: 698: 693: 688: 683: 678: 673: 668: 14648: 14357: 13755: 13563: 13554: 13505: 13451: 13410: 13361: 13320: 13271: 13230: 13195: 13168: 13127: 13091: 13040: 12999: 12958: 12909: 12866: 12825: 12784: 12735: 12683: 12637: 12588: 12544: 12500: 12451: 12408: 12394: 12363: 12322: 12278: 12243: 12208: 12165: 12124: 12089: 12022: 11979: 11930: 11925: 11890: 11860: 11856: 11822: 11768: 11724: 11678: 11626: 11577: 11528: 11487: 11459: 11391: 11379: 11348: 11336: 11301: 11250: 11193: 11158: 11121: 11109: 11074: 11025: 10912: 10861: 10820: 10771: 10722: 10673: 10624: 10575: 10521: 10472: 10423: 10369: 10328: 10287: 10235: 10183: 10129: 10088: 10047: 9985: 9925: 9889: 9830: 9773: 9728: 9635: 9630: 9613: 9594: 9553: 9502: 9453: 9439: 9396: 9353: 9296: 9261: 9220: 9163: 9114: 9093:"Translational control by MAPK signaling in long-term synaptic plasticity and memory" 9073: 9016: 9012: 8973: 8938: 8887: 8838: 8797: 8783: 8748: 8707: 8666: 8600: 8595: 8578: 8559: 8503: 8454: 8419: 8367: 8315: 8258: 8215: 8211: 8180: 8137: 8088: 8045: 8010: 7953: 7918: 7867: 7832: 7783: 7724: 7687: 7636: 7582: 7529: 7485: 7415: 7372: 7337: 7288: 7239: 7190: 7131: 7082: 7025: 6960: 6917: 6871: 6819: 6778: 6729: 6670: 6635: 6586: 6537: 6486: 6437: 6388: 6337: 6288: 6247: 6206: 6165: 6105: 6054: 6001: 5950: 5899: 5853: 5802: 5744: 5690: 5631: 5588: 5547: 5495: 5438: 5403: 5354: 5313: 5264: 5212: 5158: 5114: 5079: 5022: 4987: 4938: 4874: 4823: 4764: 4760: 4721: 4717: 4651: 4600: 4551: 4502: 4459: 4454: 4419: 4400: 4396: 4354: 4316: 4259: 4255: 4216: 4168: 4133: 4076: 4034: 3978: 3917: 3857: 3805: 3753: 3749: 3703: 3653: 3516: 3330: 2961: 2866: 2814: 2792: 2764: 2759:

mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal

2744: 2535: 2512: 2183: 2070: 1966: 1946: 1942: 1863: 1839: 171: 47: 12463: 12420: 12034: 11965: 11872: 11205: 11037: 9816: 9785: 9751:"Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention" 9308: 8466: 8270: 8227: 7965: 6972: 6929: 5911: 5643: 5034: 4776: 4733: 4612: 4563: 4514: 4366: 4271: 4088: 3956: 3765: 2162:

mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR (

203: 15692: 15687: 15661: 15589: 14386: 14377: 14307: 14298: 14244: 14235: 13892: 13495: 13487: 13441: 13400: 13392: 13351: 13310: 13261: 13222: 13158: 13119: 13081: 13071: 13030: 12989: 12948: 12921: 12901: 12856: 12815: 12774: 12766: 12725: 12717: 12673: 12627: 12619: 12578: 12534: 12490: 12443: 12398: 12390: 12353: 12312: 12270: 12235: 12200: 12155: 12116: 12079: 12069: 12014: 11969: 11961: 11920: 11910: 11852: 11812: 11758: 11714: 11668: 11616: 11608: 11567: 11559: 11518: 11449: 11371: 11328: 11318: 11291: 11281: 11240: 11232: 11185: 11148: 11101: 11064: 11017: 10902: 10892: 10851: 10810: 10802: 10761: 10753: 10712: 10704: 10663: 10655: 10614: 10606: 10565: 10557: 10511: 10503: 10462: 10454: 10413: 10405: 10359: 10318: 10277: 10269: 10225: 10217: 10173: 10163: 10119: 10078: 10037: 10029: 9975: 9967: 9937: 9917: 9879: 9869: 9820: 9812: 9765: 9718: 9710: 9625: 9584: 9543: 9533: 9492: 9484: 9443: 9435: 9408: 9388: 9343: 9335: 9288: 9251: 9210: 9202: 9153: 9145: 9104: 9063: 9055: 9028: 9008: 8985: 8965: 8928: 8918: 8877: 8869: 8828: 8787: 8779: 8738: 8697: 8656: 8646: 8612: 8590: 8549: 8539: 8493: 8446: 8409: 8401: 8357: 8349: 8305: 8297: 8254: 8250: 8207: 8172: 8127: 8119: 8080: 8057: 8037: 8000: 7992: 7945: 7908: 7898: 7859: 7822: 7814: 7773: 7765: 7736: 7716: 7677: 7669: 7626: 7618: 7572: 7562: 7519: 7475: 7465: 7427: 7407: 7364: 7327: 7319: 7278: 7270: 7229: 7221: 7180: 7170: 7121: 7113: 7072: 7064: 7015: 7007: 6952: 6909: 6861: 6853: 6809: 6768: 6764: 6760: 6719: 6709: 6662: 6625: 6617: 6576: 6568: 6527: 6517: 6476: 6468: 6427: 6419: 6378: 6368: 6327: 6319: 6278: 6237: 6196: 6155: 6147: 6095: 6087: 6044: 6034: 5991: 5983: 5942: 5891: 5843: 5833: 5792: 5734: 5680: 5670: 5623: 5578: 5537: 5485: 5477: 5450: 5430: 5393: 5385: 5344: 5303: 5295: 5284:"The role of target of rapamycin signaling networks in plant growth and metabolism" 5254: 5246: 5202: 5192: 5148: 5106: 5069: 5061: 5014: 4977: 4969: 4930: 4864: 4856: 4813: 4803: 4756: 4713: 4686: 4663: 4643: 4590: 4541: 4494: 4449: 4439: 4392: 4346: 4306: 4298: 4251: 4228: 4208: 4160: 4123: 4115: 4068: 4024: 4016: 3968: 3907: 3899: 3847: 3839: 3795: 3745: 3715: 3695: 3643: 2282: 2258: 2204: 1879: 468: 399: 343: 298: 12239: 12204: 12144:"Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells" 11563: 10610: 10152:"ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy" 6842:"Extension of chronological life span in yeast by decreased TOR pathway signaling" 6242: 6225: 5050:"The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging" 4843:"The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging" 3784:"Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells" 3632:"Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells" 15739: 15723: 15636: 15067: 14138: 14133: 14128: 13086: 12583: 12566: 12403: 12018: 11189: 11153: 11137:"TORC1 inhibition enhances immune function and reduces infections in the elderly" 11136: 10806: 10659: 10409: 10364: 10347: 10124: 10107: 10033: 9874: 9339: 9324:"Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection" 8702: 8685: 8123: 7863: 7470: 7175: 6714: 6572: 6522: 6283: 6266: 6091: 5946: 5481: 4973: 4847: 4808: 3935:

Figure 1: Domain structure of the mTOR kinase and components of mTORC1 and mTORC2

3903: 3498: 3342: 3278: 2861: 2772: 2696: 2002: 1974: 1951: 1938: 443: 227: 12623: 11891:"RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1" 10323: 10306: 9183:"Sustained translational repression by eIF2α-P mediates prion neurodegeneration" 8873: 8176: 7818: 7720: 5097:

Huang S, Houghton PJ (December 2001). "Mechanisms of resistance to rapamycins".

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National Center for Biotechnology Information, U.S. National Library of Medicine

3599:

National Center for Biotechnology Information, U.S. National Library of Medicine

2375:. Genetic reduction of mTOR expression in mice significantly increases lifespan. 1031:

positive regulation of transcription of nucleolar large rRNA by RNA polymerase I

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