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雷帕霉素机理标靶（Mechanistic target of rapamycin），常简称mTOR。为MTOR基因翻译而得的一种激酶[1][2]，mTOR为PI3K相关激酶（英语：phosphatidylinositol 3-kinase-related kinase）家族下的一员[3]。

mTOR links with other proteins and serves as a core component of two distinct protein complexes, mTOR complex 1（英语：mTORC1） and mTOR complex 2（英语：mTORC2）, which regulate different cellular processes.[4] In particular, as a core component of both complexes, mTOR functions as a serine/threonine protein kinase（英语：serine/threonine protein kinase） that regulates cell growth, cell proliferation（英语：cell proliferation）, cell motility, cell survival, protein synthesis, autophagy, and transcription.[4][5] As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptor（英语：insulin receptor）s and insulin-like growth factor 1 receptors.[6] mTORC2 has also been implicated in the control and maintenance of the actin cytoskeleton.[4][7]

发现

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The discovery of mTOR stemmed from independent studies of the natural product rapamycin by Stuart L. Schreiber, David M. Sabatini（英语：David M. Sabatini）, and Robert T. Abraham.[1][8][9] Rapamycin (sirolimus) was discovered in a soil sample from Easter Island, known locally as Rapa Nui, in the 1970s.[10] The bacterium Streptomyces hygroscopicus（英语：Streptomyces hygroscopicus）, isolated from that sample, produces an antifungal and immunosuppressive agent that researchers named rapamycin after the island.[11]

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.[12] Thus, it is used as an immunosuppressant following organ transplantation.[13] Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506（英语：FK506） in 1987. In 1989-90, FK506 and rapamycin were determined to inhibit T-cell receptor (TCR) and IL-2 receptor（英语：IL-2 receptor） signaling pathways, respectively.[14][15] The two natural products were used to discover the FK506- and rapamycin-binding proteins, including FKBP12, and to show that FKBP12–FK506 and FKBP12–rapamycin act through gain-of-function mechanisms that target distinct cellular functions. These studies established FKBP12 as the target of rapamycin, but implied that the complex interacts with another element of the mechanistic cascade.[16][17]

In 1991, calcineurin was identified as the target of FKBP12-FK506,[18] but that of FKBP12-rapamycin remained mysterious until 1994 when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues.[1][8][13] Sequence analysis of mTOR revealed similarity to the proteins encoded by the yeast dominant rapamycin resistance 1 and 2 (DRR1 and DRR2) and the target of rapamycin 1 and 2 (TOR1 and TOR2) genes, which George Livi and Michael N. Hall（英语：Michael N. Hall） had identified, respectively, in genetic screens for rapamycin resistance in 1993.

The protein now called mTOR was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini;[1][8] 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,[1] was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein. In 2009 the FRAP1 gene name was officially changed by the HUGO Gene Nomenclature Committee（英语：HUGO Gene Nomenclature Committee） (HGNC) to mTOR, which stands for mechanistic target of rapamycin.

The 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

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MTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2（英语：IGF-2）), and amino acids.[5] mTOR also senses cellular nutrient, oxygen, and energy levels.[19] The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.[20][21] Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12（英语：FKBP）.[22][23] The FKBP12（英语：FKBP）-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.[23]

复合物

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Schematic components of the mTOR complexes, mTORC1（英语：mTORC1） (left) and mTORC2（英语：mTORC2） (right). FKBP12（英语：FKBP12）, the biological target to which rapamycin binds, is a non-obligate component protein of mTORC1.[4]

MTOR is the catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2.[24] Both complexes localize to different subcellular compartments, thus affecting their activation and function.[25]

mTORC1

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主条目：mTORC1

mTOR Complex 1 (mTORC1) is composed of MTOR, regulatory-associated protein of MTOR (Raptor（英语：RPTOR）), mammalian lethal with SEC13 protein 8 (MLST8（英语：MLST8）) and the non-core components PRAS40（英语：AKT1S1） and DEPTOR（英语：DEPTOR）.[26][27] This complex functions as a nutrient/energy/redox sensor and controls protein synthesis.[5][26] 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（英语：β-hydroxy β-methylbutyric acid）), mechanical stimuli, and oxidative stress.[26][28][29]

mTORC2

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主条目：mTORC2

mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR (RICTOR（英语：RICTOR）), MLST8（英语：MLST8）, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1（英语：MAPKAP1）).[30][31] mTORC2 has been shown to function as an important regulator of the actin cytoskeleton through its stimulation of F-actin stress fibers, paxillin（英语：paxillin）, RhoA（英语：RHOA）, Rac1（英语：RAC1）, Cdc42（英语：CDC42）, and protein kinase C α (PKCα（英语：PKC alpha）).[31] mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473, thus affecting metabolism and survival.[32] Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by PDK1（英语：PDPK1） and leads to full Akt activation.[33][34] In addition, mTORC2 exhibits tyrosine protein kinase activity and phosphorylates the insulin-like growth factor 1 receptor (IGF-IR) and insulin receptor（英语：insulin receptor） (InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR.[6]

Inhibition by rapamycin

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Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). 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.[35]

Gene deletion experiments

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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（英语：NIP7）: Knockdown reduced mTORC2 activity that is indicated by decreased phosphorylation of mTORC2 substrates.[36]
  • RICTOR（英语：RICTOR）: Overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation.[37] Constitutive deletion of Rictor in mice leads to embryonic lethality,[38] 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.[35][39][40][41] Decreased Rictor expression in mice decreases male, but not female, lifespan.[42]
  • 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.[43] Genetic reduction of mTOR expression in mice significantly increases lifespan.[44]
  • PDK1（英语：Pyruvate dehydrogenase lipoamide kinase isozyme 1）: Knockout is lethal; hypomorphic allele（英语：Muller's morphs） results in smaller organ volume and organism size but normal AKT activation.[45]
  • AKT: Knockout mice experience spontaneous apoptosis (AKT1（英语：AKT1）), severe diabetes (AKT2（英语：AKT2）), small brains (AKT3（英语：AKT3）), and growth deficiency (AKT1/AKT2).[46] Mice heterozygous for AKT1 have increased lifespan.[47]
  • 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.[48][49]

临床意义

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老化

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mTOR signaling pathway.[1]

Decreased TOR activity has been found to increase life span in S. cerevisiae, C. elegans, and D. melanogaster.[50][51][52][53] The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice.[54][55][56][57][58]

It is hypothesized that some dietary regimes, like caloric restriction（英语：caloric restriction） and methionine restriction, cause lifespan extension by decreasing mTOR activity.[50][51] 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.[59] An alternative theory is mTOR signaling is an example of antagonistic pleiotropy（英语：Antagonistic pleiotropy hypothesis）, and while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. CR and methionine restriction may act in part by limiting levels of essential amino acids including leucine and methionine, which are potent activators of mTOR.[60] 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.[61]

According to the free radical theory of aging（英语：free radical theory of aging）,[62] reactive oxygen species cause damage of mitochondrial proteins and decrease ATP production. Subsequently, via ATP sensitive AMPK（英语：AMP-activated protein kinase）, the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ribosome.[12] Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration.[63] These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates glycolysis[63] and removal of dysfunctional cellular components via autophagy.[62]

Brain function

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癌症

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Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas.[64] 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（英语：PI3K）, an upstream effector of mTOR. Additionally, mTOR activity is deregulated in many cancers as a result of increased activity of PI3K（英语：PI3K） or Akt.[65] Similarly, overexpression of downstream mTOR effectors 4E-BP1（英语：4E-BP1）, S6K（英语：S6K） and eIF4E leads to poor cancer prognosis.[66] Also, mutations in TSC（英语：Tuberous sclerosis protein） protein that inhibits 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（英语：renal cell carcinoma）.[67]

Increasing mTOR activity was shown to drive cell cycle progression and increase cell proliferation mainly thanks to its effect on protein synthesis. Moreover, active mTOR supports tumor growth also indirectly by inhibiting autophagy.[68] Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A（英语：HIF1A） and supporting angiogenesis.[69] mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate - activation of glycolytic metabolism. Akt2（英语：Akt2）, a substrate of mTOR, specifically of mTORC2（英语：mTORC2）, upregulates expression of the glycolytic enzyme PKM2（英语：PKM2） thus contributing to the Warburg effect.[70]

Central nervous system disorders

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主条目：Central nervous system disorder

Autism

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MTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in autism spectrum disorders.[71]

Alzheimer’s disease

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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.[72][73][74] 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.[75] In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway, which in turn activates mTOR.[76] 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.[77][78] 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.[79][80] These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling.[81]

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.[80][82] 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.[82] In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed.[82] 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.[82][83][84] 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.[77][85][86][87] It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins.[88]

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.[80][89][90][91][92] 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.[76][93] 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.[94]

Some evidence points to mTOR’s role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy;[95] 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.[96][97][98][99][100][101] Studies using mouse models of Huntington’s disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates.[102][103] Perhaps the same treatment may be useful in clearing Aβ deposits as well.

Protein synthesis and cell growth

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mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal muscle hypertrophy（英语：muscle hypertrophy） in humans in response to both physical exercise and ingestion of certain amino acids or amino acid derivatives.[104][105] Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during muscle wasting（英语：muscle wasting） in old age, cancer cachexia, and muscle atrophy（英语：muscle atrophy） from physical inactivity（英语：sedentary lifestyle）.[104][105][106] mTORC2 activation appears to mediate neurite outgrowth in differentiated mouse neuro2a cell（英语：neuro2a cell）s.[107] Intermittent mTOR activation in prefrontal neurons by β-hydroxy β-methylbutyrate（英语：β-hydroxy β-methylbutyrate） inhibits age-related cognitive decline associated with dendritic pruning in animals, which is a phenomenon also observed in humans.[108]

 
Diagram of the molecular signaling cascades that are involved in myofibrillar（英语：myofibrillar） muscle protein synthesis and mitochondrial biogenesis（英语：mitochondrial biogenesis） in response to physical exercise and specific amino acids or their derivatives (primarily leucine and HMB（英语：Beta-Hydroxy beta-methylbutyric acid）).[104] Many amino acids derived from food protein promote the activation of mTORC1（英语：mTORC1） and increase protein synthesis by signaling through Rag GTPase（英语：Rag GTPase）s.[4][104]
Abbreviations and representations:
 · PLD: phospholipase D（英语：phospholipase D）
 · PA: phosphatidic acid
 · mTOR: mechanistic target of rapamycin
 · AMP: adenosine monophosphate
 · ATP: adenosine triphosphate
 · AMPK: AMP-activated protein kinase（英语：AMP-activated protein kinase）
 · PGC‐1α: peroxisome proliferator-activated receptor gamma coactivator-1α（英语：PGC-1α）
 · S6K1: p70S6 kinase（英语：p70S6 kinase）
 · 4EBP1: eukaryotic translation initiation factor 4E-binding protein 1（英语：EIF4EBP1）
 · eIF4E: eukaryotic translation initiation factor 4E
 · RPS6: ribosomal protein S6（英语：ribosomal protein S6）
 · eEF2: eukaryotic elongation factor 2
 · RE: resistance exercise（英语：resistance exercise）; EE: endurance exercise（英语：endurance exercise）
 · Myo: myofibrillar（英语：myofibrillar）; Mito: mitochondrial
 · AA: amino acids
 · HMB: β-hydroxy β-methylbutyric acid（英语：β-hydroxy β-methylbutyric acid）
 · ↑ represents activation
 · Τ represents inhibition
 
Resistance training（英语：Resistance training） stimulates muscle protein synthesis (MPS) for a period of up to 48 hours following exercise (shown by dotted line).[109] 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).[109]

Scleroderma

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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.[110][111] mTOR plays a role in fibrotic diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma.[3]

mTOR inhibitors as therapies

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主条目：mTOR inhibitors

mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection. Rapamycin is also related to the therapy of glycogen storage disease (GSD). 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 diseases that involve glycogen accumulation in muscle. Various natural compounds, including epigallocatechin gallate (EGCG), caffeine, curcumin, and resveratrol, have also been reported to inhibit mTOR when applied to isolated cells in culture;[20][112] however, there is as yet no evidence that these substances inhibit mTOR when taken as dietary supplements.

Some mTOR inhibitors (e.g. temsirolimus（英语：temsirolimus）, everolimus（英语：everolimus）) are beginning to be used in the treatment of cancer.[67][113] mTOR inhibitors may also be useful for treating several age-associated diseases[114] including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.[115] Ridaforolimus（英语：Ridaforolimus） is another mTOR inhibitor, currently in clinical development.

其他异名

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mTOR原称哺乳动物雷帕霉素标靶（mammalian target of rapamycin），后来因为在其他真核生物中发现该基因而改名[116]。又称为有些文献有称之为FRAP1（FK506-binding protein 12-rapamycin-associated protein 1）。

交互作用

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Mammalian target of rapamycin has been shown to interact with:[117]

参考文献

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  1. ^ 1.0 1.1 1.2 1.3 1.4 Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. June 1994, 369 (6483): 756–8. PMID 8008069. doi:10.1038/369756a0. 
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    mTOR function is mediated through two large biochemical complexes defined by their respective protein composition and have been extensively reviewed elsewhere(Dibble and Manning, 2013; Laplante and Sabatini, 2012)(Figure 1B). In brief, common to both mTOR complex 1 (mTORC1) and mTOR complex 2 (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
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Template:Serine/threonine-specific protein kinases

Category:Tor signaling pathway（英语：Category:Tor signaling pathway） Category:Aging-related proteins（英语：Category:Aging-related proteins）

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