MTOR

MTOR
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4JT6, 1AUE, 1FAP, 1NSG, 2FAP, 2GAQ, 2NPU, 2RSE, 3FAP, 4DRH, 4DRI, 4DRJ, 4FAP, 4JSN, 4JSP, 4JSV, 4JSX, 4JT5, 5FLC
Identifiers
Aliases	MTOR , FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS, mechanistic target of rapamycin, mechanistic target of rapamycin kinase
External IDs	OMIM: 601231; MGI: 1928394; HomoloGene: 3637; GeneCards: MTOR; OMA:MTOR - orthologs
Gene location (Human) Chr. Chromosome 1 (human) [1] Band 1p36.22 Start 11,106,535 bp [1] End 11,262,551 bp [1]
Gene location (Mouse) Chr. Chromosome 4 (mouse) [2] Band 4 E2|4 78.76 cM Start 148,533,068 bp [2] End 148,642,140 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gonad right hemisphere of cerebellum left testis right testis gastrocnemius muscle right frontal lobe muscle of thigh testicle ventricular zone apex of heart Top expressed in spermatid spermatocyte right kidney dentate gyrus of hippocampal formation granule cell superior frontal gyrus genital tubercle primary visual cortex muscle of thigh ventricular zone neural layer of retina More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein domain specific binding TFIIIC-class transcription factor complex binding kinase activity ATP binding protein serine/threonine kinase activity transferase activity ribosome binding protein binding protein kinase binding nucleotide binding phosphoprotein binding protein kinase activity protein-containing complex binding identical protein binding translation regulator activity Cellular component cytoplasm cytosol phosphatidylinositol 3-kinase complex membrane mitochondrion TORC1 complex organelle membrane protein-containing complex mitochondrial outer membrane endoplasmic reticulum TORC2 complex Golgi apparatus intracellular membrane-bounded organelle nucleoplasm soma PML body endoplasmic reticulum membrane Golgi membrane lysosomal membrane dendrite endomembrane system nucleus lysosome glutamatergic synapse postsynaptic cytosol Biological process germ cell development positive regulation of protein phosphorylation response to amino acid positive regulation of lipid biosynthetic process positive regulation of actin filament polymerization positive regulation of skeletal muscle hypertrophy positive regulation of granulosa cell proliferation regulation of carbohydrate utilization post-embryonic development positive regulation of dendritic spine development positive regulation of translation positive regulation of eating behavior protein phosphorylation mRNA stabilization cell projection organization regulation of glycogen biosynthetic process positive regulation of cell growth involved in cardiac muscle cell development positive regulation of neuron maturation positive regulation of glial cell proliferation cellular response to hypoxia negative regulation of cell size response to cocaine positive regulation of protein kinase B signaling cardiac muscle contraction maternal process involved in female pregnancy ruffle organization regulation of GTPase activity cardiac muscle cell development positive regulation of transcription of nucleolar large rRNA by RNA polymerase I regulation of membrane permeability response to insulin regulation of myelination regulation of fatty acid beta-oxidation regulation of osteoclast differentiation positive regulation of cholangiocyte proliferation regulation of protein kinase B signaling spinal cord development positive regulation of peptidyl-tyrosine phosphorylation social behavior protein autophosphorylation negative regulation of cholangiocyte apoptotic process regulation of brown fat cell differentiation regulation of protein kinase activity negative regulation of protein phosphorylation positive regulation of oligodendrocyte differentiation regulation of carbohydrate metabolic process regulation of actin cytoskeleton organization voluntary musculoskeletal movement phosphorylation multicellular organism growth negative regulation of muscle atrophy wound healing positive regulation of neurogenesis response to morphine positive regulation of sensory perception of pain protein catabolic process 'de novo' pyrimidine nucleobase biosynthetic process cellular response to nutrient levels energy reserve metabolic process peptidyl-threonine phosphorylation positive regulation of transcription by RNA polymerase III positive regulation of smooth muscle cell proliferation visual learning positive regulation of myotube differentiation positive regulation of cell death positive regulation of endothelial cell proliferation negative regulation of iodide transmembrane transport cardiac muscle tissue development positive regulation of nitric oxide biosynthetic process regulation of response to food heart morphogenesis positive regulation of neuron death cardiac cell development negative regulation of protein ubiquitination brain development positive regulation of gene expression long-term memory heart valve morphogenesis peptidyl-serine phosphorylation positive regulation of neuron projection development regulation of cellular response to heat positive regulation of lamellipodium assembly positive regulation of stress fiber assembly signal transduction regulation of protein phosphorylation negative regulation of macroautophagy anoikis TOR signaling DNA repair regulation of cell size negative regulation of autophagy positive regulation of epithelial to mesenchymal transition regulation of macroautophagy cellular response to amino acid starvation positive regulation of keratinocyte migration cellular response to amino acid stimulus cellular response to leucine positive regulation of wound healing, spreading of epidermal cells cellular response to leucine starvation cellular response to starvation TORC1 signaling growth regulation of cell growth response to nutrient activation of protein kinase B activity T-helper 1 cell lineage commitment response to activity positive regulation of phosphoprotein phosphatase activity negative regulation of calcineurin-NFAT signaling cascade regulation of translation at synapse, modulating synaptic transmission positive regulation of cytoplasmic translational initiation response to nutrient levels Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2475 56717 Ensembl ENSG00000198793 ENSMUSG00000028991 UniProt P42345 Q9JLN9 RefSeq (mRNA) NM_004958 NM_001386500 NM_001386501 NM_020009 RefSeq (protein) NP_004949 NP_064393 Location (UCSC) Chr 1: 11.11 – 11.26 Mb Chr 4: 148.53 – 148.64 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The mammalian target of rapamycin (mTOR), ^[5] also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. ^{[6] [7] [8]} mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. ^[9]

mTOR links with other proteins and serves as a core component of two distinct protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes. ^[10] In particular, as a core component of both complexes, mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. ^{[10] [11]} As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors. ^[12] mTORC2 has also been implicated in the control and maintenance of the actin cytoskeleton. ^{[10] [13]}

Discovery

Rapa Nui (Easter Island - Chile)

The study of TOR (Target Of Rapamycin) originated in the 1960s with an expedition to Easter Island (known by the island inhabitants as Rapa Nui), with the goal of identifying natural products from plants and soil with possible therapeutic potential. In 1972, Suren Sehgal identified a small molecule, from the soil bacterium Streptomyces hygroscopicus , that he purified and initially reported to possess potent antifungal activity. He named it rapamycin, noting its original source and activity. ^{[14] [15]} 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.

Subsequent history

The discovery of TOR and mTOR stemmed from independent studies of the natural product rapamycin by Joseph Heitman, Rao Movva, and Michael N. Hall in 1991; ^[16] by David M. Sabatini, Hediye Erdjument-Bromage, Mary Lui, Paul Tempst, and Solomon H. Snyder in 1994; ^[7] 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. ^[8] In 1991, working in yeast, Hall and colleagues identified the TOR1 and TOR2 genes. ^[16] In 1993, Robert Cafferkey, George Livi, and colleagues, and Jeannette Kunz, Michael N. Hall, and colleagues independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes. ^{[17] [18]}

Rapamycin arrests fungal activity at the G1 phase of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in T-lymphocytes. ^[19] Thus, it is used as an immunosuppressant following organ transplantation. ^[20] Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506 (later called Tacrolimus) in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit T-cell receptor (TCR) and IL-2 receptor signaling pathways, respectively. ^{[21] [22]} The two natural products were used to discover the FK506- and rapamycin-binding proteins, including FKBP12, 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. ^{[23] [24]} These studies implicated FKBP12 as a possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade. ^{[25] [26]}

In 1991, calcineurin was identified as the target of FKBP12-FK506. ^[27] 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, ^{[16] [28]} followed by studies in 1994 when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues. ^{[6] [7] [20]} Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast target of rapamycin 1 and 2 (TOR1 and TOR2) genes, which Joseph Heitman, Rao Movva, and Michael N. Hall had identified in August 1991 and May 1993. Independently, George Livi and colleagues later reported the same genes, which they called dominant rapamycin resistance 1 and 2 (DRR1 and DRR2), in studies published in October 1993.

The protein, now called mTOR, was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini; ^{[6] [7]} FRAP1 was used as its official gene symbol in humans. Because of these different names, mTOR, which had been first used by Robert T. Abraham, ^[6] 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 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 Spalentor. ^[29] "mTOR" initially meant "mammalian target of rapamycin", but the meaning of the "m" was later changed to "mechanistic". ^[30] 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 HUGO Gene Nomenclature Committee (HGNC) to mTOR, which stands for mechanistic target of rapamycin. ^[31]

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.

Function

mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids. ^[11] mTOR also senses cellular nutrient, oxygen, and energy levels. ^[32] 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, ^[33] and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers. ^{[34] [35]} Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12. ^{[36] [37]} The FKBP12–rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity. ^[37]

In plants

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. ^[38] Plant species have TOR proteins in the protein kinase and FKBP-rapamycin binding (FRB) domains that share a similar amino acid sequence to mTOR in mammals. ^[39]

Role of mTOR in plants

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 mRNA and the growth of cells within the plant. However, the TORC1 complex activation stops catabolic processes such as autophagy from occurring. ^[38] 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. ^[40] mTOR is also found to be highly involved in developing embryo tissue in plants. ^[39]

Complexes

Schematic components of the mTOR complexes, mTORC1 (left) and mTORC2 (right). FKBP12, the biological target to which rapamycin binds, is a non-obligate component protein of mTORC1.

mTOR is the catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2. ^[41] The two complexes localize to different subcellular compartments, thus affecting their activation and function. ^[42] Upon activation by Rheb, mTORC1 localizes to the Ragulator-Rag complex on the lysosome surface where it then becomes active in the presence of sufficient amino acids. ^{[43] [44]}

mTORC1

Main article: mTORC1

mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (mLST8) and the non-core components PRAS40 and DEPTOR. ^{[45] [46]} This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. ^{[11] [45]} The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress. ^{[45] [47] [48]}

mTORC2

Main article: mTORC2

mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR (RICTOR), MLST8, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1). ^{[49] [50]} mTORC2 has been shown to function as an important regulator of the actin cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα). ^[50] mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473, thus affecting metabolism and survival. ^[51] Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by PDK1 and leads to full Akt activation. ^{[52] [53]} In addition, mTORC2 exhibits tyrosine protein kinase activity and phosphorylates the insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR. ^[12]

Inhibition by rapamycin

Main article: Sirolimus

Rapamycin (Sirolimus) inhibits mTORC1, resulting in the suppression of cellular senescence. ^[54] This appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Suppression of insulin resistance by sirtuins accounts for at least some of this effect. ^[55] Impaired sirtuin 3 leads to mitochondrial dysfunction. ^[56]

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. ^[57]

Gene deletion experiments

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 knockdowns and knockouts and were found to produce the following phenotypes:

• NIP7: Knockdown reduced mTORC2 activity that is indicated by decreased phosphorylation of mTORC2 substrates. ^[58]
• RICTOR: Overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation. ^[59] Constitutive deletion of Rictor in mice leads to embryonic lethality, ^[60] 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. ^{[57] [61] [62] [63]} Decreased Rictor expression in mice decreases male, but not female, lifespan. ^[64]
• mTOR: Inhibition of mTORC1 and mTORC2 by PP242 [2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol] leads to autophagy or apoptosis; inhibition of mTORC2 alone by PP242 prevents phosphorylation of Ser-473 site on AKT and arrests the cells in G1 phase of the cell cycle. ^[65] Genetic reduction of mTOR expression in mice significantly increases lifespan. ^[66]
• PDK1: Knockout is lethal; hypomorphic allele results in smaller organ volume and organism size but normal AKT activation. ^[67]
• AKT: Knockout mice experience spontaneous apoptosis (AKT1), severe diabetes (AKT2), small brains (AKT3), and growth deficiency (AKT1/AKT2). ^[68] Mice heterozygous for AKT1 have increased lifespan. ^[69]
• TOR1, the S. cerevisiae 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 yeast. ^{[70] [71]}

Clinical significance

Aging

mTOR signaling pathway

Decreased TOR activity has been found to increase life span in S. cerevisiae , C. elegans, and D. melanogaster . ^{[72] [73] [74] [75]} The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice. ^{[76] [77] [78] [79] [80]}

It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity. ^{[72] [73]} 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. ^[81] An alternative theory is mTOR signaling is an example of antagonistic pleiotropy, 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 essential amino acids including leucine and methionine, which are potent activators of mTOR. ^[82] The administration of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway in the hypothalamus. ^[83]

According to the free radical theory of aging, ^[84] reactive oxygen species cause damage to mitochondrial proteins and decrease ATP production. Subsequently, via ATP sensitive AMPK, the mTOR pathway is inhibited and ATP-consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ribosome. ^[19] Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration. ^[85] 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 autophagy. ^[84]

mTOR is a key initiator of the senescence-associated secretory phenotype (SASP). ^[86] Interleukin 1 alpha (IL1A) is found on the surface of senescent cells where it contributes to the production of SASP factors due to a positive feedback loop with NF-κB. ^{[87] [88]} Translation of mRNA for IL1A is highly dependent upon mTOR activity. ^[89] mTOR activity increases levels of IL1A, mediated by MAPKAPK2. ^[87] mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors. ^[90]

Cancer

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. ^[91] Reasons for constitutive activation are several. Among the most common are mutations in tumor suppressor PTEN gene. PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of PI3K, an upstream effector of mTOR. Additionally, mTOR activity is deregulated in many cancers as a result of increased activity of PI3K or Akt. ^[92] Similarly, overexpression of downstream mTOR effectors 4E-BP1, S6K1, S6K2 and eIF4E leads to poor cancer prognosis. ^[93] Also, mutations in TSC proteins that inhibit the activity of mTOR may lead to a condition named tuberous sclerosis complex, which exhibits as benign lesions and increases the risk of renal cell carcinoma. ^[94]

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 autophagy. ^[95] Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis. ^[96] mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of glycolytic metabolism. Akt2, a substrate of mTOR, specifically of mTORC2, upregulates expression of the glycolytic enzyme PKM2 thus contributing to the Warburg effect. ^[97]

Central nervous system disorders / Brain function

Main article: Central nervous system disorder

Autism

mTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in autism spectrum disorders. ^[98]

Alzheimer's disease

mTOR signaling intersects with Alzheimer's disease (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. ^{[99] [100] [101]} 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. ^[102] In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway, which in turn activates mTOR. ^[103] 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. ^{[104] [105]} 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. ^{[106] [107]} These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling. ^[108]

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. ^{[107] [109]} Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling. ^[109] In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed. ^[109] 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. ^{[109] [110] [111]} Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD.

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. ^{[104] [112] [113] [114]} It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins. ^[115]

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. ^{[107] [116] [117] [118] [119]} Both protein over- and 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. ^{[103] [120]} 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. ^[121]

Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy; ^[122] 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, including AD. ^{[123] [124] [125] [126] [127] [128]} Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates. ^{[129] [130]} Perhaps the same treatment may be useful in clearing Aβ deposits as well.

Lymphoproliferative diseases

Hyperactive mTOR pathways have been identified in certain lymphoproliferative diseases such as autoimmune lymphoproliferative syndrome (ALPS), ^[131] multicentric Castleman disease, ^[132] and post-transplant lymphoproliferative disorder (PTLD). ^[133]

Protein synthesis and cell growth

mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal muscle hypertrophy in humans in response to both physical exercise and ingestion of certain amino acids or amino acid derivatives. ^{[134] [135]} Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during muscle wasting in old age, cancer cachexia, and muscle atrophy from physical inactivity. ^{[134] [135] [136]} mTORC2 activation appears to mediate neurite outgrowth in differentiated mouse neuro2a cells. ^[137] Intermittent mTOR activation in prefrontal neurons by β-hydroxy β-methylbutyrate inhibits age-related cognitive decline associated with dendritic pruning in animals, which is a phenomenon also observed in humans. ^[138]

Diagram of the molecular signaling cascades that are involved in myofibrillar muscle protein synthesis and mitochondrial biogenesis in response to physical exercise and specific amino acids or their derivatives (primarily leucine and HMB). ^[134] Many amino acids derived from food protein promote the activation of mTORC1 and increase protein synthesis by signaling through Rag GTPases. ^{[10] [134]}

Abbreviations and representations:

 •PLD: phospholipase D
 •PA: phosphatidic acid
 •mTOR: mechanistic target of rapamycin
 •AMP: adenosine monophosphate
 •ATP: adenosine triphosphate
 •AMPK: AMP-activated protein kinase
 •PGC‐1α: peroxisome proliferator-activated receptor gamma coactivator-1α
 •S6K1: p70S6 kinase
 •4EBP1: eukaryotic translation initiation factor 4E-binding protein 1
 •eIF4E: eukaryotic translation initiation factor 4E
 •RPS6: ribosomal protein S6
 •eEF2: eukaryotic elongation factor 2
 •RE: resistance exercise; EE: endurance exercise
 •Myo: myofibrillar; Mito: mitochondrial
 •AA: amino acids
 •HMB: β-hydroxy β-methylbutyric acid
 •↑ represents activation
 •Τ represents inhibition

Resistance training stimulates muscle protein synthesis (MPS) for a period of up to 48 hours following exercise (shown by dotted line). ^[139] 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 lines). ^[139]

Lysosomal damage inhibits mTOR and induces autophagy

Active mTORC1 is positioned on lysosomes. mTOR is inhibited ^[140] when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading bacteria, membrane-permeant chemicals yielding osmotically active products (this type of injury can be modeled using membrane-permeant dipeptide precursors that polymerize in lysosomes), amyloid protein aggregates (see above section on Alzheimer's disease) and cytoplasmic organic or inorganic inclusions including urate crystals and crystalline silica. ^[140] The process of mTOR inactivation following lysosomal/endomembrane is mediated by the protein complex termed GALTOR. ^[140] At the heart of GALTOR ^[140] is galectin-8, a member of β-galactoside binding superfamily of cytosolic lectins termed galectins, which recognizes lysosomal membrane damage by binding to the exposed glycans 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 SLC38A9, RRAGA/RRAGB, and LAMTOR1, inhibiting Ragulator's (LAMTOR1-5 complex) guanine nucleotide exchange function- ^[140]

TOR is a negative regulator of autophagy in general, best studied during response to starvation, ^{[141] [142] [143] [144] [145]} which is a metabolic response. During lysosomal damage however, mTOR inhibition activates autophagy response in its quality control function, leading to the process termed lysophagy ^[146] that removes damaged lysosomes. At this stage another galectin, galectin-3, interacts with TRIM16 to guide selective autophagy of damaged lysosomes. ^{[147] [148]} TRIM16 gathers ULK1 and principal components (Beclin 1 and ATG16L1) of other complexes (Beclin 1-VPS34-ATG14 and ATG16L1-ATG5-ATG12) initiating autophagy, ^[148] many of them being under negative control of mTOR directly such as the ULK1-ATG13 complex, ^{[143] [144] [145]} or indirectly, such as components of the class III PI3K (Beclin 1, ATG14 and VPS34) since they depend on activating phosphorylations by ULK1 when it is not inhibited by mTOR. These autophagy-driving components physically and functionally link up with each other integrating all processes necessary for autophagosomal formation: (i) the ULK1-ATG13-FIP200/RB1CC1 complex associates with the LC3B/GABARAP conjugation machinery through direct interactions between FIP200/RB1CC1 and ATG16L1, ^{[149] [150] [151]} (ii) ULK1-ATG13-FIP200/RB1CC1 complex associates with the Beclin 1-VPS34-ATG14 via direct interactions between ATG13's HORMA domain and ATG14, ^[152] (iii) ATG16L1 interacts with WIPI2, which binds to PI3P, the enzymatic product of the class III PI3K Beclin 1-VPS34-ATG14. ^[153] Thus, mTOR inactivation, initiated through GALTOR ^[140] upon lysosomal damage, plus a simultaneous activation via galectin-9 (which also recognizes lysosomal membrane breach) of AMPK ^[140] that directly phosphorylates and activates key components (ULK1, ^[154] Beclin 1 ^[155] ) of the autophagy systems listed above and further inactivates mTORC1, ^{[156] [157]} allows for strong autophagy induction and autophagic removal of damaged lysosomes.

Additionally, several types of ubiquitination events parallel and complement the galectin-driven processes: Ubiquitination of TRIM16-ULK1-Beclin-1 stabilizes these complexes to promote autophagy activation as described above. ^[148] ATG16L1 has an intrinsic binding affinity for ubiquitin ^[151] ); whereas ubiquitination by a glycoprotein-specific FBXO27-endowed ubiquitin ligase of several damage-exposed glycosylated lysosomal membrane proteins such as LAMP1, LAMP2, GNS/N-acetylglucosamine-6-sulfatase, TSPAN6/tetraspanin-6, PSAP/prosaposin, and TMEM192/transmembrane protein 192 ^[158] may contribute to the execution of lysophagy via autophagic receptors such as p62/SQSTM1, which is recruited during lysophagy, ^[151] or other to be determined functions.

Scleroderma

Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma) that affects internal organs in its more severe forms. ^{[159] [160]} mTOR plays a role in fibrotic diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma. ^[9]

Smith-Kingsmore syndrome

A rare gain-of-function mutation causes Smith-Kingsmore syndrome. ^[161]

mTOR inhibitors as therapies

Main article: mTOR inhibitors

Transplantation

mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection.

Glycogen storage disease

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 glycogen storage disease that involve glycogen accumulation in muscle.

Anti-cancer

There are two primary mTOR inhibitors used in the treatment of human cancers, temsirolimus and everolimus. mTOR inhibitors have found use in the treatment of a variety of malignancies, including renal cell carcinoma (temsirolimus) and pancreatic cancer, breast cancer, and renal cell carcinoma (everolimus). ^[162] The complete mechanism of these agents is not clear, but they are thought to function by impairing tumour angiogenesis and causing impairment of the G1/S transition. ^[163]

Anti-aging

mTOR inhibitors may be useful for treating/preventing several age-associated conditions, ^[164] including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. ^[165] After a short-term treatment with the mTOR inhibitors dactolisib and everolimus, in elderly (65 and older), treated subjects had a reduced number of infections over the course of a year. ^[166]

Various natural compounds, including epigallocatechin gallate (EGCG), caffeine, curcumin, berberine, quercetin, resveratrol and pterostilbene, have been reported to inhibit mTOR when applied to isolated cells in culture. ^{[167] [168] [169]} As yet no high quality evidence exists that these substances inhibit mTOR signaling or extend lifespan when taken as dietary supplements by humans, despite encouraging results in animals such as fruit flies and mice. Various trials are ongoing. ^{[170] [171]}

Interactions

Mechanistic target of rapamycin has been shown to interact with: ^[172]

• ABL1, ^[173]
• AKT1, ^{[52] [174] [175]}
• IGF-IR, ^[12]
• InsR, ^[12]
• CLIP1, ^[176]
• EIF3F ^[177]
• EIF4EBP1, ^{[45] [178] [179] [180] [181] [182] [183] [184]}
• FKBP1A, ^{[13] [50] [185] [186] [187] [188]}
• GPHN, ^[189]
• KIAA1303, ^{[13] [45] [49] [50] [85] [178] [179] [180] [190] [191] [192] [193] [194] [195] [196] [197] [198] [199] [200] [201]}
• PRKCD, ^[202]
• RHEB, ^{[181] [203] [204] [205]}
• RICTOR, ^{[13] [49] [50] [192] [198] [200] [201]}
• RPS6KB1, ^{[45] [179] [181] [182] [183] [197] [200] [206] [207] [208] [209] [210] [211] [212] [213]}
• STAT1, ^[214]
• STAT3, ^{[215] [216]}
• Two-pore channels: TPCN1; TPCN2, ^[217] and
• UBQLN1. ^[218]

References

1. GRCh38: Ensembl release 89: ENSG00000198793 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000028991 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Sabers CJ, Martin MM, Brunn GJ, et al. (Jan 1995). "Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells". J. Biol. Chem. 270 (2): 815–22. doi: 10.1074/jbc.270.2.815 . PMID   7822316.
6. Brown EJ, Albers MW, Shin TB, et al. (June 1994). "A mammalian protein targeted by G1-arresting rapamycin-receptor complex". Nature. 369 (6483): 756–8. Bibcode:1994Natur.369..756B. doi:10.1038/369756a0. PMID   8008069. S2CID   4359651.
7. 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". Cell. 78 (1): 35–43. doi:10.1016/0092-8674(94)90570-3. PMID   7518356. S2CID   33647539.
8. Sabers CJ, Martin MM, Brunn GJ, et al. (January 1995). "Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells". The Journal of Biological Chemistry. 270 (2): 815–22. doi: 10.1074/jbc.270.2.815 . PMID   7822316.
9. Mitra A, Luna JI, Marusina AI, et al. (November 2015). "Dual mTOR Inhibition Is Required to Prevent TGF-β-Mediated Fibrosis: Implications for Scleroderma". The Journal of Investigative Dermatology. 135 (11): 2873–6. doi:10.1038/jid.2015.252. PMC   4640976 . PMID   26134944.
10. Lipton JO, Sahin M (October 2014). "The neurology of mTOR". Neuron. 84 (2): 275–291. doi:10.1016/j.neuron.2014.09.034. PMC   4223653 . PMID   25374355. 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 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. ...
    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 (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.
    Figure 1: Domain structure of the mTOR kinase and components of mTORC1 and mTORC2
    Figure 2: The mTOR Signaling Pathway
11. Hay N, Sonenberg N (August 2004). "Upstream and downstream of mTOR". Genes & Development. 18 (16): 1926–45. doi: 10.1101/gad.1212704 . PMID   15314020.
12. Yin Y, Hua H, Li M, et al. (January 2016). "mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR". Cell Research. 26 (1): 46–65. doi:10.1038/cr.2015.133. PMC   4816127 . PMID   26584640.
13. Jacinto E, Loewith R, Schmidt A, et al. (November 2004). "Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive". Nature Cell Biology. 6 (11): 1122–8. doi:10.1038/ncb1183. PMID   15467718. S2CID   13831153.
14. Powers T (November 2022). Kellogg D (ed.). "The origin story of rapamycin: systemic bias in biomedical research and cold war politics". Molecular Biology of the Cell. 33 (13). doi:10.1091/mbc.E22-08-0377. PMC   9634974 . PMID   36228182.
15. Sehgal SN, Baker H, Vézina C (October 1975). "Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization". The Journal of Antibiotics. 28 (10): 727–732. doi:10.7164/antibiotics.28.727. PMID   1102509.
16. Heitman J, Movva NR, Hall MN (August 1991). "Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast". Science. 253 (5022): 905–9. Bibcode:1991Sci...253..905H. doi:10.1126/science.1715094. PMID   1715094. S2CID   9937225.
17. 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". Cell. 73 (3): 585–596. doi:10.1016/0092-8674(93)90144-F. PMID   8387896. S2CID   42926249.
18. Cafferkey R, Young PR, McLaughlin MM, et al. (October 1993). "Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity". Mol Cell Biol. 13 (10): 6012–23. doi:10.1128/MCB.13.10.6012. PMC   364661 . PMID   8413204.
19. Magnuson B, Ekim B, Fingar DC (January 2012). "Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signaling networks". The Biochemical Journal. 441 (1): 1–21. doi:10.1042/BJ20110892. PMID   22168436. S2CID   12932678.
20. Abraham RT, Wiederrecht GJ (1996). "Immunopharmacology of rapamycin". Annual Review of Immunology. 14: 483–510. doi:10.1146/annurev.immunol.14.1.483. PMID   8717522.
21. Bierer BE, Mattila PS, Standaert RF, et al. (December 1990). "Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin". Proceedings of the National Academy of Sciences of the United States of America. 87 (23): 9231–5. Bibcode:1990PNAS...87.9231B. doi: 10.1073/pnas.87.23.9231 . PMC   55138 . PMID   2123553.
22. Bierer BE, Somers PK, Wandless TJ, et al. (October 1990). "Probing immunosuppressant action with a nonnatural immunophilin ligand". Science. 250 (4980): 556–9. Bibcode:1990Sci...250..556B. doi:10.1126/science.1700475. PMID   1700475. S2CID   11123023.
23. Dumont FJ, Melino MR, Staruch MJ, et al. (February 1990). "The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells". J Immunol. 144 (4): 1418–24. doi: 10.4049/jimmunol.144.4.1418 . PMID   1689353. S2CID   44256944.
24. Dumont FJ, Staruch MJ, Koprak SL, et al. (January 1990). "Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin". J Immunol. 144 (1): 251–8. doi: 10.4049/jimmunol.144.1.251 . PMID   1688572. S2CID   13201695.
25. Harding MW, Galat A, Uehling DE, et al. (October 1989). "A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase". Nature. 341 (6244): 758–60. Bibcode:1989Natur.341..758H. doi:10.1038/341758a0. PMID   2477715. S2CID   4349152.
26. Fretz H, Albers MW, Galat A, et al. (February 1991). "Rapamycin and FK506 binding proteins (immunophilins)". Journal of the American Chemical Society. 113 (4): 1409–1411. doi:10.1021/ja00004a051.
27. Liu J, Farmer JD, Lane WS, et al. (August 1991). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes". Cell. 66 (4): 807–15. doi:10.1016/0092-8674(91)90124-H. PMID   1715244. S2CID   22094672.
28. 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". Cell. 73 (3): 585–596. doi:10.1016/0092-8674(93)90144-F. PMID   8387896. S2CID   42926249.
29. Heitman J (November 2015). "On the discovery of TOR as the target of rapamycin". PLOS Pathogens. 11 (11): e1005245. doi: 10.1371/journal.ppat.1005245 . PMC   4634758 . PMID   26540102.
30. Kennedy BK, Lamming DW (2016). "The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging". Cell Metabolism . 23 (6): 990–1003. doi:10.1016/j.cmet.2016.05.009. PMC   4910876 . PMID   27304501.
31. "Symbol report for MTOR". HGNC data for MTOR. HUGO Gene Nomenclature Committee. September 1, 2020. Retrieved 2020-12-17.
32. Tokunaga C, Yoshino K, Yonezawa K (January 2004). "mTOR integrates amino acid- and energy-sensing pathways". Biochemical and Biophysical Research Communications. 313 (2): 443–6. doi:10.1016/j.bbrc.2003.07.019. PMID   14684182.
33. Wipperman MF, Montrose DC, Gotto AM, et al. (2019). "Mammalian Target of Rapamycin: A Metabolic Rheostat for Regulating Adipose Tissue Function and Cardiovascular Health". The American Journal of Pathology. 189 (3): 492–501. doi:10.1016/j.ajpath.2018.11.013. PMC   6412382 . PMID   30803496.
34. Beevers CS, Li F, Liu L, et al. (August 2006). "Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells". International Journal of Cancer. 119 (4): 757–64. doi:10.1002/ijc.21932. PMID   16550606. S2CID   25454463.
35. Kennedy BK, Lamming DW (June 2016). "The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging". Cell Metabolism. 23 (6): 990–1003. doi:10.1016/j.cmet.2016.05.009. PMC   4910876 . PMID   27304501.
36. Huang S, Houghton PJ (December 2001). "Mechanisms of resistance to rapamycins". Drug Resistance Updates. 4 (6): 378–91. doi:10.1054/drup.2002.0227. PMID   12030785.
37. Huang S, Bjornsti MA, Houghton PJ (2003). "Rapamycins: mechanism of action and cellular resistance". Cancer Biology & Therapy. 2 (3): 222–32. doi: 10.4161/cbt.2.3.360 . PMID   12878853.
38. Ingargiola C, Turqueto Duarte G, Robaglia C, et al. (October 2020). "The Plant Target of Rapamycin: A Conduc TOR of Nutrition and Metabolism in Photosynthetic Organisms". Genes. 11 (11): 1285. doi: 10.3390/genes11111285 . PMC   7694126 . PMID   33138108.
39. Shi L, Wu Y, Sheen J (July 2018). "TOR signaling in plants: conservation and innovation". Development. 145 (13). doi:10.1242/dev.160887. PMC   6053665 . PMID   29986898.
40. Xiong Y, Sheen J (February 2014). "The role of target of rapamycin signaling networks in plant growth and metabolism". Plant Physiology. 164 (2): 499–512. doi:10.1104/pp.113.229948. PMC   3912084 . PMID   24385567.
41. Wullschleger S, Loewith R, Hall MN (February 2006). "TOR signaling in growth and metabolism". Cell. 124 (3): 471–84. doi: 10.1016/j.cell.2006.01.016 . PMID   16469695.
42. Betz C, Hall MN (November 2013). "Where is mTOR and what is it doing there?". The Journal of Cell Biology. 203 (4): 563–74. doi:10.1083/jcb.201306041. PMC   3840941 . PMID   24385483.
43. Groenewoud MJ, Zwartkruis FJ (August 2013). "Rheb and Rags come together at the lysosome to activate mTORC1". Biochemical Society Transactions. 41 (4): 951–5. doi:10.1042/bst20130037. PMID   23863162. S2CID   8237502.
44. Efeyan A, Zoncu R, Sabatini DM (September 2012). "Amino acids and mTORC1: from lysosomes to disease". Trends in Molecular Medicine. 18 (9): 524–33. doi:10.1016/j.molmed.2012.05.007. PMC   3432651 . PMID   22749019.
45. Kim DH, Sarbassov DD, Ali SM, et al. (July 2002). "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery". Cell. 110 (2): 163–75. doi: 10.1016/S0092-8674(02)00808-5 . PMID   12150925.
46. Kim DH, Sarbassov DD, Ali SM, et al. (April 2003). "GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR". Molecular Cell. 11 (4): 895–904. doi: 10.1016/S1097-2765(03)00114-X . PMID   12718876.
47. Fang Y, Vilella-Bach M, Bachmann R, et al. (November 2001). "Phosphatidic acid-mediated mitogenic activation of mTOR signaling". Science. 294 (5548): 1942–5. Bibcode:2001Sci...294.1942F. doi:10.1126/science.1066015. PMID   11729323. S2CID   44444716.
48. Bond P (March 2016). "Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance". J. Int. Soc. Sports Nutr. 13: 8. doi: 10.1186/s12970-016-0118-y . PMC   4774173 . PMID   26937223.
49. Frias MA, Thoreen CC, Jaffe JD, et al. (September 2006). "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s". Current Biology. 16 (18): 1865–70. Bibcode:2006CBio...16.1865F. doi: 10.1016/j.cub.2006.08.001 . PMID   16919458.
50. Sarbassov DD, Ali SM, Kim DH, et al. (July 2004). "Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton". Current Biology. 14 (14): 1296–302. Bibcode:2004CBio...14.1296D. doi: 10.1016/j.cub.2004.06.054 . PMID   15268862.
51. Betz C, Stracka D, Prescianotto-Baschong C, et al. (July 2013). "Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology". Proceedings of the National Academy of Sciences of the United States of America. 110 (31): 12526–34. doi: 10.1073/pnas.1302455110 . PMC   3732980 . PMID   23852728.
52. Sarbassov DD, Guertin DA, Ali SM, et al. (February 2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science. 307 (5712): 1098–101. Bibcode:2005Sci...307.1098S. doi:10.1126/science.1106148. PMID   15718470. S2CID   45837814.
53. 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". Science. 279 (5351): 710–4. Bibcode:1998Sci...279..710S. doi:10.1126/science.279.5351.710. PMID   9445477.
54. Carosi JM, Fourrier C, Bensalem J, et al. (2022). "The mTOR-lysosome axis at the centre of ageing". FEBS Open Bio . 12 (4): 739–757. doi:10.1002/2211-5463.13347. PMC   8972043 . PMID   34878722.
55. Zhou S, Tang X, Chen H (2018). "Sirtuins and Insulin Resistance". Frontiers in Endocrinology . 9: 748. doi: 10.3389/fendo.2018.00748 . PMC   6291425 . PMID   30574122.
56. Baechle JJ, Chen N, Winer DA (2023). "Chronic inflammation and the hallmarks of aging". Molecular Metabolism . 74: 101755. doi:10.1016/j.molmet.2023.101755. PMC   10359950 . PMID   37329949.
57. Lamming DW, Ye L, Katajisto P, et al. (March 2012). "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity". Science. 335 (6076): 1638–43. Bibcode:2012Sci...335.1638L. doi:10.1126/science.1215135. PMC   3324089 . PMID   22461615.
58. Zinzalla V, Stracka D, Oppliger W, et al. (March 2011). "Activation of mTORC2 by association with the ribosome". Cell. 144 (5): 757–68. doi: 10.1016/j.cell.2011.02.014 . PMID   21376236.
59. Zhang F, Zhang X, Li M, et al. (November 2010). "mTOR complex component Rictor interacts with PKCzeta and regulates cancer cell metastasis". Cancer Research. 70 (22): 9360–70. doi: 10.1158/0008-5472.CAN-10-0207 . PMID   20978191.
60. Guertin DA, Stevens DM, Thoreen CC, et al. (December 2006). "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". Developmental Cell. 11 (6): 859–71. doi: 10.1016/j.devcel.2006.10.007 . PMID   17141160.
61. Gu Y, Lindner J, Kumar A, et al. (March 2011). "Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size". Diabetes. 60 (3): 827–37. doi:10.2337/db10-1194. PMC   3046843 . PMID   21266327.
62. Lamming DW, Demirkan G, Boylan JM, et al. (January 2014). "Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2)". FASEB Journal. 28 (1): 300–15. doi: 10.1096/fj.13-237743 . PMC   3868844 . PMID   24072782.
63. Kumar A, Lawrence JC, Jung DY, et al. (June 2010). "Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism". Diabetes. 59 (6): 1397–406. doi:10.2337/db09-1061. PMC   2874700 . PMID   20332342.
64. Lamming DW, Mihaylova MM, Katajisto P, et al. (October 2014). "Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan". Aging Cell. 13 (5): 911–7. doi:10.1111/acel.12256. PMC   4172536 . PMID   25059582.
65. Feldman ME, Apsel B, Uotila A, et al. (February 2009). "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2". PLOS Biology. 7 (2): e38. doi: 10.1371/journal.pbio.1000038 . PMC   2637922 . PMID   19209957.
66. Wu JJ, Liu J, Chen EB, et al. (September 2013). "Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression". Cell Reports. 4 (5): 913–20. doi:10.1016/j.celrep.2013.07.030. PMC   3784301 . PMID   23994476.
67. Lawlor MA, Mora A, Ashby PR, et al. (July 2002). "Essential role of PDK1 in regulating cell size and development in mice". The EMBO Journal. 21 (14): 3728–38. doi:10.1093/emboj/cdf387. PMC   126129 . PMID   12110585.
68. Yang ZZ, Tschopp O, Baudry A, et al. (April 2004). "Physiological functions of protein kinase B/Akt". Biochemical Society Transactions. 32 (Pt 2): 350–4. doi:10.1042/BST0320350. PMID   15046607.
69. Nojima A, Yamashita M, Yoshida Y, et al. (2013-01-01). "Haploinsufficiency of akt1 prolongs the lifespan of mice". PLOS ONE. 8 (7): e69178. Bibcode:2013PLoSO...869178N. doi: 10.1371/journal.pone.0069178 . PMC   3728301 . PMID   23935948.
70. Crespo JL, Hall MN (December 2002). "Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae". Microbiology and Molecular Biology Reviews. 66 (4): 579–91, table of contents. doi:10.1128/mmbr.66.4.579-591.2002. PMC   134654 . PMID   12456783.
71. Peter GJ, Düring L, Ahmed A (March 2006). "Carbon catabolite repression regulates amino acid permeases in Saccharomyces cerevisiae via the TOR signaling pathway". The Journal of Biological Chemistry. 281 (9): 5546–52. doi: 10.1074/jbc.M513842200 . PMID   16407266.
72. Powers RW, Kaeberlein M, Caldwell SD, et al. (January 2006). "Extension of chronological life span in yeast by decreased TOR pathway signaling". Genes & Development. 20 (2): 174–84. doi:10.1101/gad.1381406. PMC   1356109 . PMID   16418483.
73. Kaeberlein M, Powers RW, Steffen KK, et al. (November 2005). "Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients". Science. 310 (5751): 1193–6. Bibcode:2005Sci...310.1193K. doi:10.1126/science.1115535. PMID   16293764. S2CID   42188272.
74. 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". Development. 131 (16): 3897–906. doi:10.1242/dev.01255. PMID   15253933. S2CID   10377667.
75. Kapahi P, Zid BM, Harper T, et al. (May 2004). "Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway". Current Biology. 14 (10): 885–90. Bibcode:2004CBio...14..885K. doi:10.1016/j.cub.2004.03.059. PMC   2754830 . PMID   15186745.
76. Harrison DE, Strong R, Sharp ZD, et al. (July 2009). "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice". Nature. 460 (7253): 392–5. Bibcode:2009Natur.460..392H. doi:10.1038/nature08221. PMC   2786175 . PMID   19587680.
77. Miller RA, Harrison DE, Astle CM, et al. (June 2014). "Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction". Aging Cell. 13 (3): 468–77. doi:10.1111/acel.12194. PMC   4032600 . PMID   24341993.
78. Fok WC, Chen Y, Bokov A, et al. (2014-01-01). "Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome". PLOS ONE. 9 (1): e83988. Bibcode:2014PLoSO...983988F. doi: 10.1371/journal.pone.0083988 . PMC   3883653 . PMID   24409289.
79. Arriola Apelo SI, Pumper CP, Baar EL, et al. (July 2016). "Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 71 (7): 876–81. doi:10.1093/gerona/glw064. PMC   4906329 . PMID   27091134.
80. Popovich IG, Anisimov VN, Zabezhinski MA, et al. (May 2014). "Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin". Cancer Biology & Therapy. 15 (5): 586–92. doi:10.4161/cbt.28164. PMC   4026081 . PMID   24556924.
81. Baar EL, Carbajal KA, Ong IM, et al. (February 2016). "Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice". Aging Cell. 15 (1): 155–66. doi:10.1111/acel.12425. PMC   4717274 . PMID   26695882.
82. Caron A, Richard D, Laplante M (Jul 2015). "The Roles of mTOR Complexes in Lipid Metabolism". Annual Review of Nutrition. 35: 321–48. doi:10.1146/annurev-nutr-071714-034355. PMID   26185979.
83. Cota D, Proulx K, Smith KA, et al. (May 2006). "Hypothalamic mTOR signaling regulates food intake". Science. 312 (5775): 927–30. Bibcode:2006Sci...312..927C. doi:10.1126/science.1124147. PMID   16690869. S2CID   6526786.
84. Kriete A, Bosl WJ, Booker G (June 2010). "Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses". PLOS Computational Biology. 6 (6): e1000820. Bibcode:2010PLSCB...6E0820K. doi: 10.1371/journal.pcbi.1000820 . PMC   2887462 . PMID   20585546.
85. Schieke SM, Phillips D, McCoy JP, et al. (September 2006). "The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity". The Journal of Biological Chemistry. 281 (37): 27643–52. doi: 10.1074/jbc.M603536200 . PMID   16847060.
86. Yessenkyzy A, Saliev T, Zhanaliyeva M, et al. (2020). "Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research". Nutrients . 12 (5): 1344. doi: 10.3390/nu12051344 . PMC   7285205 . PMID   32397145.
87. Laberge R, Sun Y, Orjalo AV, et al. (2015). "MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation". Nature Cell Biology . 17 (8): 1049–1061. doi:10.1038/ncb3195. PMC   4691706 . PMID   26147250.
88. Wang R, Yu Z, Sunchu B, et al. (2017). "Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism". Aging Cell . 16 (3): 564–574. doi:10.1111/acel.12587. PMC   5418203 . PMID   28371119.
89. Wang R, Sunchu B, Perez VI (2017). "Rapamycin and the inhibition of the secretory phenotype". Experimental Gerontology . 94: 89–92. doi:10.1016/j.exger.2017.01.026. PMID   28167236. S2CID   4960885.
90. Weichhart T (2018). "mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review". Gerontology . 84 (2): 127–134. doi:10.1159/000484629. PMC   6089343 . PMID   29190625.
91. Xu K, Liu P, Wei W (December 2014). "mTOR signaling in tumorigenesis". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1846 (2): 638–54. doi:10.1016/j.bbcan.2014.10.007. PMC   4261029 . PMID   25450580.
92. Guertin DA, Sabatini DM (August 2005). "An expanding role for mTOR in cancer". Trends in Molecular Medicine. 11 (8): 353–61. doi:10.1016/j.molmed.2005.06.007. PMID   16002336.
93. Pópulo H, Lopes JM, Soares P (2012). "The mTOR signalling pathway in human cancer". International Journal of Molecular Sciences. 13 (2): 1886–918. doi: 10.3390/ijms13021886 . PMC   3291999 . PMID   22408430.
94. Easton JB, Houghton PJ (October 2006). "mTOR and cancer therapy". Oncogene. 25 (48): 6436–46. doi:10.1038/sj.onc.1209886. PMID   17041628. S2CID   19250234.
95. Zoncu R, Efeyan A, Sabatini DM (January 2011). "mTOR: from growth signal integration to cancer, diabetes and ageing". Nature Reviews Molecular Cell Biology. 12 (1): 21–35. doi:10.1038/nrm3025. PMC   3390257 . PMID   21157483.
96. Thomas GV, Tran C, Mellinghoff IK, et al. (January 2006). "Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer". Nature Medicine. 12 (1): 122–7. doi:10.1038/nm1337. PMID   16341243. S2CID   1853822.
97. 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". Biochemical Society Transactions. 41 (4): 917–22. doi:10.1042/BST20130034. PMID   23863156.
98. Tang G, Gudsnuk K, Kuo SH, et al. (September 2014). "Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits". Neuron. 83 (5): 1131–43. doi:10.1016/j.neuron.2014.07.040. PMC   4159743 . PMID   25155956.
99. Rosner M, Hanneder M, Siegel N, et al. (June 2008). "The mTOR pathway and its role in human genetic diseases". Mutation Research. 659 (3): 284–92. Bibcode:2008MRRMR.659..284R. doi:10.1016/j.mrrev.2008.06.001. PMID   18598780.
100. 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". The FEBS Journal. 272 (16): 4211–20. doi:10.1111/j.1742-4658.2005.04833.x. PMID   16098202. S2CID   43085490.
101. 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". Brain Research. 1168 (1168): 97–105. doi:10.1016/j.brainres.2007.06.075. PMID   17706618. S2CID   54255848.
102. Selkoe DJ (September 2008). "Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior". Behavioural Brain Research. 192 (1): 106–13. doi:10.1016/j.bbr.2008.02.016. PMC   2601528 . PMID   18359102.
103. Oddo S (January 2012). "The role of mTOR signaling in Alzheimer disease". Frontiers in Bioscience. 4 (1): 941–52. doi:10.2741/s310. PMC   4111148 . PMID   22202101.
104. An WL, Cowburn RF, Li L, et al. (August 2003). "Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease". The American Journal of Pathology. 163 (2): 591–607. doi:10.1016/S0002-9440(10)63687-5. PMC   1868198 . PMID   12875979.
105. Zhang F, Beharry ZM, Harris TE, et al. (May 2009). "PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells". Cancer Biology & Therapy. 8 (9): 846–53. doi:10.4161/cbt.8.9.8210. PMID   19276681. S2CID   22153842.
106. Koo EH, Squazzo SL (July 1994). "Evidence that production and release of amyloid beta-protein involves the endocytic pathway". The Journal of Biological Chemistry. 269 (26): 17386–9. doi: 10.1016/S0021-9258(17)32449-3 . PMID   8021238.
107. Caccamo A, Majumder S, Richardson A, et al. (April 2010). "Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments". The Journal of Biological Chemistry. 285 (17): 13107–20. doi: 10.1074/jbc.M110.100420 . PMC   2857107 . PMID   20178983.
108. Lafay-Chebassier C, Paccalin M, Page G, et al. (July 2005). "mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease". Journal of Neurochemistry. 94 (1): 215–25. doi: 10.1111/j.1471-4159.2005.03187.x . PMID   15953364. S2CID   8464608.
109. Caccamo A, Maldonado MA, Majumder S, et al. (March 2011). "Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism". The Journal of Biological Chemistry. 286 (11): 8924–32. doi: 10.1074/jbc.M110.180638 . PMC   3058958 . PMID   21266573.
110. Sancak Y, Thoreen CC, Peterson TR, et al. (March 2007). "PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase". Molecular Cell. 25 (6): 903–15. doi: 10.1016/j.molcel.2007.03.003 . PMID   17386266.
111. Wang L, Harris TE, Roth RA, et al. (July 2007). "PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding". The Journal of Biological Chemistry. 282 (27): 20036–44. doi: 10.1074/jbc.M702376200 . PMID   17510057.
112. Pei JJ, Hugon J (December 2008). "mTOR-dependent signalling in Alzheimer's disease". Journal of Cellular and Molecular Medicine. 12 (6B): 2525–32. doi:10.1111/j.1582-4934.2008.00509.x. PMC   3828871 . PMID   19210753.
113. Meske V, Albert F, Ohm TG (January 2008). "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". The Journal of Biological Chemistry. 283 (1): 100–9. doi: 10.1074/jbc.M704292200 . PMID   17971449.
114. Janssens V, Goris J (February 2001). "Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling". The Biochemical Journal. 353 (Pt 3): 417–39. doi:10.1042/0264-6021:3530417. PMC   1221586 . PMID   11171037.
115. Morita T, Sobue K (October 2009). "Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway". The Journal of Biological Chemistry. 284 (40): 27734–45. doi: 10.1074/jbc.M109.008177 . PMC   2785701 . PMID   19648118.
116. Puighermanal E, Marsicano G, Busquets-Garcia A, et al. (September 2009). "Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling". Nature Neuroscience. 12 (9): 1152–8. doi:10.1038/nn.2369. PMID   19648913. S2CID   9584832.
117. Tischmeyer W, Schicknick H, Kraus M, et al. (August 2003). "Rapamycin-sensitive signalling in long-term consolidation of auditory cortex-dependent memory". The European Journal of Neuroscience. 18 (4): 942–50. doi:10.1046/j.1460-9568.2003.02820.x. PMID   12925020. S2CID   2780242.
118. Hoeffer CA, Klann E (February 2010). "mTOR signaling: at the crossroads of plasticity, memory and disease". Trends in Neurosciences. 33 (2): 67–75. doi:10.1016/j.tins.2009.11.003. PMC   2821969 . PMID   19963289.
119. Kelleher RJ, Govindarajan A, Jung HY, et al. (February 2004). "Translational control by MAPK signaling in long-term synaptic plasticity and memory". Cell. 116 (3): 467–79. doi: 10.1016/S0092-8674(04)00115-1 . PMID   15016380.
120. Ehninger D, Han S, Shilyansky C, et al. (August 2008). "Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis". Nature Medicine. 14 (8): 843–8. doi:10.1038/nm1788. PMC   2664098 . PMID   18568033.
121. Moreno JA, Radford H, Peretti D, et al. (May 2012). "Sustained translational repression by eIF2α-P mediates prion neurodegeneration". Nature. 485 (7399): 507–11. Bibcode:2012Natur.485..507M. doi:10.1038/nature11058. PMC   3378208 . PMID   22622579.
122. Díaz-Troya S, Pérez-Pérez ME, Florencio FJ, et al. (October 2008). "The role of TOR in autophagy regulation from yeast to plants and mammals". Autophagy. 4 (7): 851–65. doi: 10.4161/auto.6555 . PMID   18670193.
123. McCray BA, Taylor JP (December 2008). "The role of autophagy in age-related neurodegeneration". Neuro-Signals. 16 (1): 75–84. doi:10.1159/000109761. PMID   18097162. S2CID   13591350.
124. Nedelsky NB, Todd PK, Taylor JP (December 2008). "Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1782 (12): 691–9. doi:10.1016/j.bbadis.2008.10.002. PMC   2621359 . PMID   18930136.
125. Rubinsztein DC (October 2006). "The roles of intracellular protein-degradation pathways in neurodegeneration". Nature. 443 (7113): 780–6. Bibcode:2006Natur.443..780R. doi:10.1038/nature05291. PMID   17051204. S2CID   4411895.
126. Oddo S (April 2008). "The ubiquitin-proteasome system in Alzheimer's disease". Journal of Cellular and Molecular Medicine. 12 (2): 363–73. doi:10.1111/j.1582-4934.2008.00276.x. PMC   3822529 . PMID   18266959.
127. Li X, Li H, Li XJ (November 2008). "Intracellular degradation of misfolded proteins in polyglutamine neurodegenerative diseases". Brain Research Reviews. 59 (1): 245–52. doi:10.1016/j.brainresrev.2008.08.003. PMC   2577582 . PMID   18773920.
128. Caccamo A, Majumder S, Deng JJ, et al. (October 2009). "Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability". The Journal of Biological Chemistry. 284 (40): 27416–24. doi: 10.1074/jbc.M109.031278 . PMC   2785671 . PMID   19651785.
129. Ravikumar B, Vacher C, Berger Z, et al. (June 2004). "Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease". Nature Genetics. 36 (6): 585–95. doi: 10.1038/ng1362 . PMID   15146184.
130. Rami A (October 2009). "Review: autophagy in neurodegeneration: firefighter and/or incendiarist?". Neuropathology and Applied Neurobiology. 35 (5): 449–61. doi: 10.1111/j.1365-2990.2009.01034.x . PMID   19555462.
131. 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. https://doi.org/10.1182/blood-2015-11-685024
132. Arenas, Daniel J., et al. "Increased mTOR activation in idiopathic multicentric Castleman disease." Blood 135.19 (2020): 1673-1684. https://doi.org/10.1182/blood.2019002792
133. El-Salem, Mouna, et al. "Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders." Laboratory Investigation 87.1 (2007): 29-39. https://doi.org/10.1038/labinvest.3700494
134. Brook MS, Wilkinson DJ, Phillips BE, et al. (January 2016). "Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise". Acta Physiologica. 216 (1): 15–41. doi:10.1111/apha.12532. PMC   4843955 . PMID   26010896.
135. Brioche T, Pagano AF, Py G, et al. (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention" (PDF). Molecular Aspects of Medicine. 50: 56–87. doi:10.1016/j.mam.2016.04.006. PMID   27106402. S2CID   29717535.
136. Drummond MJ, Dreyer HC, Fry CS, et al. (April 2009). "Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling". Journal of Applied Physiology. 106 (4): 1374–84. doi:10.1152/japplphysiol.91397.2008. PMC   2698645 . PMID   19150856.
137. Salto R, Vílchez JD, Girón MD, et al. (2015). "β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells". PLOS ONE. 10 (8): e0135614. Bibcode:2015PLoSO..1035614S. doi: 10.1371/journal.pone.0135614 . PMC   4534402 . PMID   26267903.
138. 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". Neurobiology of Aging. 40: 78–85. doi:10.1016/j.neurobiolaging.2016.01.004. PMID   26973106. S2CID   3953100.
139. Phillips SM (May 2014). "A brief review of critical processes in exercise-induced muscular hypertrophy". Sports Med. 44 (Suppl 1): S71 –S77. doi:10.1007/s40279-014-0152-3. PMC   4008813 . PMID   24791918.
140. Jia J, Abudu YP, Claude-Taupin A, et al. (April 2018). "Galectins Control mTOR in Response to Endomembrane Damage". Molecular Cell. 70 (1): 120–135.e8. doi:10.1016/j.molcel.2018.03.009. PMC   5911935 . PMID   29625033.
141. Noda T, Ohsumi Y (February 1998). "Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast". The Journal of Biological Chemistry. 273 (7): 3963–6. doi: 10.1074/jbc.273.7.3963 . PMID   9461583.
142. Dubouloz F, Deloche O, Wanke V, et al. (July 2005). "The TOR and EGO protein complexes orchestrate microautophagy in yeast". Molecular Cell. 19 (1): 15–26. doi: 10.1016/j.molcel.2005.05.020 . PMID   15989961.
143. Ganley IG, Lam du H, Wang J, et al. (May 2009). "ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy". The Journal of Biological Chemistry. 284 (18): 12297–305. doi: 10.1074/jbc.M900573200 . PMC   2673298 . PMID   19258318.
144. Jung CH, Jun CB, Ro SH, et al. (April 2009). "ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery". Molecular Biology of the Cell. 20 (7): 1992–2003. doi:10.1091/mbc.e08-12-1249. PMC   2663920 . PMID   19225151.
145. Hosokawa N, Hara T, Kaizuka T, et al. (April 2009). "Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy". Molecular Biology of the Cell. 20 (7): 1981–91. doi:10.1091/mbc.e08-12-1248. PMC   2663915 . PMID   19211835.
146. Hasegawa J, Maejima I, Iwamoto R, et al. (March 2015). "Selective autophagy: lysophagy". Methods. 75: 128–32. doi: 10.1016/j.ymeth.2014.12.014 . PMID   25542097.
147. Fraiberg M, Elazar Z (October 2016). "A TRIM16-Galactin3 Complex Mediates Autophagy of Damaged Endomembranes". Developmental Cell. 39 (1): 1–2. doi: 10.1016/j.devcel.2016.09.025 . PMID   27728777.
148. Chauhan S, Kumar S, Jain A, et al. (October 2016). "TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis". Developmental Cell. 39 (1): 13–27. doi:10.1016/j.devcel.2016.08.003. PMC   5104201 . PMID   27693506.
149. Nishimura T, Kaizuka T, Cadwell K, et al. (March 2013). "FIP200 regulates targeting of Atg16L1 to the isolation membrane". EMBO Reports. 14 (3): 284–91. doi:10.1038/embor.2013.6. PMC   3589088 . PMID   23392225.
150. Gammoh N, Florey O, Overholtzer M, et al. (February 2013). "Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy". Nature Structural & Molecular Biology. 20 (2): 144–9. doi:10.1038/nsmb.2475. PMC   3565010 . PMID   23262492.
151. Fujita N, Morita E, Itoh T, et al. (October 2013). "Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin". The Journal of Cell Biology. 203 (1): 115–28. doi:10.1083/jcb.201304188. PMC   3798248 . PMID   24100292.
152. Park JM, Jung CH, Seo M, et al. (2016-03-03). "The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14". Autophagy. 12 (3): 547–64. doi:10.1080/15548627.2016.1140293. PMC   4835982 . PMID   27046250.
153. Dooley HC, Razi M, Polson HE, et al. (July 2014). "WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1". Molecular Cell. 55 (2): 238–52. doi:10.1016/j.molcel.2014.05.021. PMC   4104028 . PMID   24954904.
154. Kim J, Kundu M, Viollet B, et al. (February 2011). "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1". Nature Cell Biology. 13 (2): 132–41. doi:10.1038/ncb2152. PMC   3987946 . PMID   21258367.
155. Kim J, Kim YC, Fang C, et al. (January 2013). "Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy". Cell. 152 (1–2): 290–303. doi:10.1016/j.cell.2012.12.016. PMC   3587159 . PMID   23332761.
156. Gwinn DM, Shackelford DB, Egan DF, et al. (April 2008). "AMPK phosphorylation of raptor mediates a metabolic checkpoint". Molecular Cell. 30 (2): 214–26. doi:10.1016/j.molcel.2008.03.003. PMC   2674027 . PMID   18439900.
157. Inoki K, Zhu T, Guan KL (November 2003). "TSC2 mediates cellular energy response to control cell growth and survival". Cell. 115 (5): 577–90. doi: 10.1016/S0092-8674(03)00929-2 . PMID   14651849.
158. Yoshida Y, Yasuda S, Fujita T, et al. (August 2017). "FBXO27 directs damaged lysosomes for autophagy". Proceedings of the National Academy of Sciences of the United States of America. 114 (32): 8574–8579. doi: 10.1073/pnas.1702615114 . PMC   5559013 . PMID   28743755.
159. Jimenez SA, Cronin PM, Koenig AS, et al. (15 February 2012). Varga J, Talavera F, Goldberg E, Mechaber AJ, Diamond HS (eds.). "Scleroderma". Medscape Reference. WebMD. Retrieved 5 March 2014.
160. Hajj-ali RA (June 2013). "Systemic Sclerosis". Merck Manual Professional. Merck Sharp & Dohme Corp. Retrieved 5 March 2014.
161. "Smith-Kingsmore syndrome: MedlinePlus Genetics". medlineplus.gov. Retrieved 16 January 2025.
162. "Mammalian target of rapamycin (mTOR) inhibitors in solid tumours". Pharmaceutical Journal. Retrieved 2018-10-18.
163. Faivre S, Kroemer G, Raymond E (August 2006). "Current development of mTOR inhibitors as anticancer agents". Nature Reviews. Drug Discovery. 5 (8): 671–88. doi:10.1038/nrd2062. PMID   16883305. S2CID   27952376.
164. Hasty P (February 2010). "Rapamycin: the cure for all that ails". Journal of Molecular Cell Biology. 2 (1): 17–9. doi: 10.1093/jmcb/mjp033 . PMID   19805415.
165. Bové J, Martínez-Vicente M, Vila M (August 2011). "Fighting neurodegeneration with rapamycin: mechanistic insights". Nature Reviews. Neuroscience. 12 (8): 437–52. doi:10.1038/nrn3068. PMID   21772323. S2CID   205506774.
166. Mannick JB, Morris M, Hockey HP, et al. (July 2018). "TORC1 inhibition enhances immune function and reduces infections in the elderly". Science Translational Medicine. 10 (449): eaaq1564. doi: 10.1126/scitranslmed.aaq1564 . PMID   29997249.
167. Estrela JM, Ortega A, Mena S, et al. (2013). "Pterostilbene: Biomedical applications". Critical Reviews in Clinical Laboratory Sciences. 50 (3): 65–78. doi:10.3109/10408363.2013.805182. PMID   23808710. S2CID   45618964.
168. McCubrey JA, Lertpiriyapong K, Steelman LS, et al. (June 2017). "Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs". Aging. 9 (6): 1477–1536. doi:10.18632/aging.101250. PMC   5509453 . PMID   28611316.
169. Malavolta M, Bracci M, Santarelli L, et al. (2018). "Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy". Mediators of Inflammation. 2018: 4159013. doi: 10.1155/2018/4159013 . PMC   5829354 . PMID   29618945.
170. 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". Biogerontology. 20 (5): 583–603. doi:10.1007/s10522-019-09817-2. PMID   31187283. S2CID   184483900.
171. Li W, Qin L, Feng R, et al. (July 2019). "Emerging senolytic agents derived from natural products". Mechanisms of Ageing and Development. 181: 1–6. doi:10.1016/j.mad.2019.05.001. PMID   31077707. S2CID   147704626.
172. "mTOR protein interactors". Human Protein Reference Database . Johns Hopkins University and the Institute of Bioinformatics. Archived from the original on 2015-06-28. Retrieved 2010-12-06.
173. Kumar V, Sabatini D, Pandey P, et al. (April 2000). "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". The Journal of Biological Chemistry. 275 (15): 10779–87. doi: 10.1074/jbc.275.15.10779 . PMID   10753870.
174. 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". Cancer Research. 60 (13): 3504–13. PMID   10910062.
175. Cheng SW, Fryer LG, Carling D, et al. (April 2004). "Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status". The Journal of Biological Chemistry. 279 (16): 15719–22. doi: 10.1074/jbc.C300534200 . PMID   14970221.
176. Choi JH, Bertram PG, Drenan R, et al. (October 2002). "The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase". EMBO Reports. 3 (10): 988–94. doi:10.1093/embo-reports/kvf197. PMC   1307618 . PMID   12231510.
177. Harris TE, Chi A, Shabanowitz J, et al. (April 2006). "mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin". The EMBO Journal. 25 (8): 1659–68. doi:10.1038/sj.emboj.7601047. PMC   1440840 . PMID   16541103.
178. Schalm SS, Fingar DC, Sabatini DM, et al. (May 2003). "TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function". Current Biology. 13 (10): 797–806. Bibcode:2003CBio...13..797S. doi: 10.1016/S0960-9822(03)00329-4 . PMID   12747827.
179. Hara K, Maruki Y, Long X, et al. (July 2002). "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action". Cell. 110 (2): 177–89. doi: 10.1016/S0092-8674(02)00833-4 . PMID   12150926.
180. Wang L, Rhodes CJ, Lawrence JC (August 2006). "Activation of mammalian target of rapamycin (mTOR) by insulin is associated with stimulation of 4EBP1 binding to dimeric mTOR complex 1". The Journal of Biological Chemistry. 281 (34): 24293–303. doi: 10.1074/jbc.M603566200 . PMID   16798736.
181. Long X, Lin Y, Ortiz-Vega S, et al. (April 2005). "Rheb binds and regulates the mTOR kinase". Current Biology. 15 (8): 702–13. Bibcode:2005CBio...15..702L. doi: 10.1016/j.cub.2005.02.053 . PMID   15854902.
182. 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". Genes to Cells. 5 (9): 765–75. doi:10.1046/j.1365-2443.2000.00365.x. PMID   10971657. S2CID   39048740.
183. Burnett PE, Barrow RK, Cohen NA, et al. (February 1998). "RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1". Proceedings of the National Academy of Sciences of the United States of America. 95 (4): 1432–7. Bibcode:1998PNAS...95.1432B. doi: 10.1073/pnas.95.4.1432 . PMC   19032 . PMID   9465032.
184. Wang X, Beugnet A, Murakami M, et al. (April 2005). "Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins". Molecular and Cellular Biology. 25 (7): 2558–72. doi:10.1128/MCB.25.7.2558-2572.2005. PMC   1061630 . PMID   15767663.
185. Choi J, Chen J, Schreiber SL, et al. (July 1996). "Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP". Science. 273 (5272): 239–42. Bibcode:1996Sci...273..239C. doi:10.1126/science.273.5272.239. PMID   8662507. S2CID   27706675.
186. Luker KE, Smith MC, Luker GD, et al. (August 2004). "Kinetics of regulated protein-protein interactions revealed with firefly luciferase complementation imaging in cells and living animals". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12288–93. Bibcode:2004PNAS..10112288L. doi: 10.1073/pnas.0404041101 . PMC   514471 . PMID   15284440.
187. Banaszynski LA, Liu CW, Wandless TJ (April 2005). "Characterization of the FKBP.rapamycin.FRB ternary complex". Journal of the American Chemical Society. 127 (13): 4715–21. doi:10.1021/ja043277y. PMID   15796538.
188. Sabers CJ, Martin MM, Brunn GJ, et al. (January 1995). "Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells". The Journal of Biological Chemistry. 270 (2): 815–22. doi: 10.1074/jbc.270.2.815 . PMID   7822316.
189. Sabatini DM, Barrow RK, Blackshaw S, et al. (May 1999). "Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling". Science. 284 (5417): 1161–4. Bibcode:1999Sci...284.1161S. doi:10.1126/science.284.5417.1161. PMID   10325225.
190. Ha SH, Kim DH, Kim IS, et al. (December 2006). "PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals". Cellular Signalling. 18 (12): 2283–91. doi:10.1016/j.cellsig.2006.05.021. PMID   16837165.
191. Buerger C, DeVries B, Stambolic V (June 2006). "Localization of Rheb to the endomembrane is critical for its signaling function". Biochemical and Biophysical Research Communications. 344 (3): 869–80. doi:10.1016/j.bbrc.2006.03.220. PMID   16631613.
192. Jacinto E, Facchinetti V, Liu D, et al. (October 2006). "SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity". Cell. 127 (1): 125–37. doi: 10.1016/j.cell.2006.08.033 . PMID   16962653.
193. McMahon LP, Yue W, Santen RJ, et al. (January 2005). "Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex". Molecular Endocrinology. 19 (1): 175–83. doi: 10.1210/me.2004-0305 . PMID   15459249.
194. 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". Genes to Cells. 9 (4): 359–66. doi:10.1111/j.1356-9597.2004.00727.x. hdl: 20.500.14094/D1002969 . PMID   15066126. S2CID   24814691.
195. 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". Virchows Archiv. 443 (1): 78–86. doi:10.1007/s00428-003-0804-4. PMID   12719976. S2CID   21552704.
196. Choi KM, McMahon LP, Lawrence JC (May 2003). "Two motifs in the translational repressor PHAS-I required for efficient phosphorylation by mammalian target of rapamycin and for recognition by raptor". The Journal of Biological Chemistry. 278 (22): 19667–73. doi: 10.1074/jbc.M301142200 . PMID   12665511.
197. Nojima H, Tokunaga C, Eguchi S, et al. (May 2003). "The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif". The Journal of Biological Chemistry. 278 (18): 15461–4. doi: 10.1074/jbc.C200665200 . PMID   12604610.
198. Sarbassov DD, Ali SM, Sengupta S, et al. (April 2006). "Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB". Molecular Cell. 22 (2): 159–68. doi: 10.1016/j.molcel.2006.03.029 . PMID   16603397.
199. Tzatsos A, Kandror KV (January 2006). "Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation". Molecular and Cellular Biology. 26 (1): 63–76. doi:10.1128/MCB.26.1.63-76.2006. PMC   1317643 . PMID   16354680.
200. Sarbassov DD, Sabatini DM (November 2005). "Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex". The Journal of Biological Chemistry. 280 (47): 39505–9. doi: 10.1074/jbc.M506096200 . PMID   16183647.
201. Yang Q, Inoki K, Ikenoue T, et al. (October 2006). "Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity". Genes & Development. 20 (20): 2820–32. doi:10.1101/gad.1461206. PMC   1619946 . PMID   17043309.
202. Kumar V, Pandey P, Sabatini D, et al. (March 2000). "Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation". The EMBO Journal. 19 (5): 1087–97. doi:10.1093/emboj/19.5.1087. PMC   305647 . PMID   10698949.
203. Long X, Ortiz-Vega S, Lin Y, et al. (June 2005). "Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency". The Journal of Biological Chemistry. 280 (25): 23433–6. doi: 10.1074/jbc.C500169200 . PMID   15878852.
204. Smith EM, Finn SG, Tee AR, et al. (May 2005). "The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses". The Journal of Biological Chemistry. 280 (19): 18717–27. doi: 10.1074/jbc.M414499200 . PMID   15772076.
205. Bernardi R, Guernah I, Jin D, et al. (August 2006). "PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR". Nature. 442 (7104): 779–85. Bibcode:2006Natur.442..779B. doi:10.1038/nature05029. PMID   16915281. S2CID   4427427.
206. Saitoh M, Pullen N, Brennan P, et al. (May 2002). "Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site". The Journal of Biological Chemistry. 277 (22): 20104–12. doi: 10.1074/jbc.M201745200 . PMID   11914378.
207. Chiang GG, Abraham RT (July 2005). "Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase". The Journal of Biological Chemistry. 280 (27): 25485–90. doi: 10.1074/jbc.M501707200 . PMID   15899889.
208. Holz MK, Blenis J (July 2005). "Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase". The Journal of Biological Chemistry. 280 (28): 26089–93. doi: 10.1074/jbc.M504045200 . PMID   15905173.
209. Isotani S, Hara K, Tokunaga C, et al. (November 1999). "Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro". The Journal of Biological Chemistry. 274 (48): 34493–8. doi: 10.1074/jbc.274.48.34493 . hdl: 20.500.14094/D1002182 . PMID   10567431.
210. 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". Biochemical and Biophysical Research Communications. 332 (1): 304–10. doi:10.1016/j.bbrc.2005.04.117. PMID   15896331.
211. Ali SM, Sabatini DM (May 2005). "Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site". The Journal of Biological Chemistry. 280 (20): 19445–8. doi: 10.1074/jbc.C500125200 . PMID   15809305.
212. Edinger AL, Linardic CM, Chiang GG, et al. (December 2003). "Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells". Cancer Research. 63 (23): 8451–60. PMID   14679009.
213. Leone M, Crowell KJ, Chen J, et al. (August 2006). "The FRB domain of mTOR: NMR solution structure and inhibitor design". Biochemistry. 45 (34): 10294–302. doi:10.1021/bi060976+. PMID   16922504.
214. Kristof AS, Marks-Konczalik J, Billings E, et al. (September 2003). "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". The Journal of Biological Chemistry. 278 (36): 33637–44. doi: 10.1074/jbc.M301053200 . PMID   12807916.
215. Yokogami K, Wakisaka S, Avruch J, et al. (January 2000). "Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR". Current Biology. 10 (1): 47–50. Bibcode:2000CBio...10...47Y. doi: 10.1016/S0960-9822(99)00268-7 . PMID   10660304.
216. Kusaba H, Ghosh P, Derin R, et al. (January 2005). "Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR)". The Journal of Biological Chemistry. 280 (2): 1037–43. doi: 10.1074/jbc.M405204200 . PMID   15522880.
217. Cang C, Zhou Y, Navarro B, et al. (February 2013). "mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state". Cell. 152 (4): 778–90. doi:10.1016/j.cell.2013.01.023. PMC   3908667 . PMID   23394946.
218. Wu S, Mikhailov A, Kallo-Hosein H, et al. (January 2002). "Characterization of ubiquilin 1, an mTOR-interacting protein". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1542 (1–3): 41–56. doi: 10.1016/S0167-4889(01)00164-1 . PMID   11853878.

Further reading

• Saxton RA, Sabatini DM (March 2017). "mTOR Signaling in Growth, Metabolism, and Disease". Cell. 168 (6): 960–976. doi:10.1016/j.cell.2017.02.004. PMC   5394987 . PMID   28283069.

External links

• mTOR+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• "mTOR Signaling Pathway in Pathway Interaction Database". National Cancer Institute. Archived from the original on 2013-03-18. Retrieved 2015-10-18.
• Overview of all the structural information available in the PDB for UniProt : P42345 (Serine/threonine-protein kinase mTOR) at the PDBe-KB .