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Template:PBB The mammalian target of rapamycin (mTOR), also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP1), is a protein that in humans is encoded by the MTOR gene.[1][2] mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.[3][4] mTOR belongs to the phosphatidylinositol 3-kinase-related kinase protein family.

Discovery and history

mTOR is the mammalian target of rapamycin. Rapamycin was discovered in a soil sample from Easter Island, known locally as Rapa Nui, in the 1970s.[5] In that sample, the bacterium Streptomyces hygroscopicus made an antifungal, which researchers named rapamycin after the island. [6]

Rapamycin arrested fungal activity at the G1 phase of the cell cycle. In rats, it suppressed the immune system by blocking the G1 to S phase transition in T-lymphocytes.[7] In humans, it is used as an immunosuppressant following organ transplantation.[8]

Saccharomyces cerevisiae can develop resistance to rapamycin, when one of three genes is knocked out.[9] Two of the genes were called targets of rapamycin (TOR). The third gene was already known as Fpr1. Fpr1 is the ortholog of FKBP12 binding protein in the TOR complexes.[10] In 1994, the mammalian target of rapamycin (mTOR) was identified as the rapamycin target in mammals by David M. Sabatini and Solomon H. Snyder (Johns Hopkins University)[11] and Stuart L. Schreiber (Harvard University).[1]

Function

mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids.[3] mTOR also senses cellular nutrient, oxygen, and energy levels.[12] The mTOR pathway is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.[4] Rapamycin is a bacterial product that can inhibit mTOR by associating with its intracellular receptor FKBP12.[13][14] The FKBP12-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.[14]

mTOR stands for mammalian Target Of Rapamycin and was named based on the precedent that TOR was first discovered via genetic and molecular studies of rapamycin-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of rapamycin and provided robust support that the FKBP12-rapamycin complex binds to and inhibits the cellular functions of Tor1 and Tor2.

Complexes

mTOR is the catalytic subunit of two molecular complexes: mTORC1 and mTORC2.[15]

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 recently identified partners PRAS40 and DEPTOR.[16][17] This complex is characterized by the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis.[3][16] The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.[16][18]

mTORC2

Main article: mTORC2

mTOR Complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive companion of mTOR (RICTOR), GβL, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1).[19][20] mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα).[20] mTORC2 also appears to possess the activity of a previously elusive protein known as "PDK2". mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue S473 . Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation;[21][22] curcumin inhibits both by preventing phosphorylation of the serine.[4]

Rapamycin action on mTORC1 and mTORC2

Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-lengthening in animal studies). Rapamycin also acts on mTORC2. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin also associated with rapamycin.[23]

Physiological significance (KO phenotypes)

The mTORC2 signaling pathway is less clearly defined than the mTORC1 signaling pathway. Therefore, performing knockout experiments is a good way to shed light on more specific molecules and their roles in this pathway. Protein function inhibition using knockdowns and knockouts were found to produce the following phenotypes:

  • NIP7: knockdown reduced mTORC2 activity which is indicated by decreased phosphorylation of mTORC2 substrates.[24]
  • RICTOR: overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation.[25]
  • 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.[26]
  • PDK1: knockout is lethal; hypomorphic allele results in smaller organ volume and organism size, but normal AKT activation.[27]
  • AKT: knockout mice experience spontaneous apoptosis (AKT1), severe diabetes (AKT2), small brains (AKT3), and growth deficiency (AKT1/AKT2) [28]
  • 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.[29][30]

Clinical significance

Aging

mTOR signaling pathway.[1]

Decreased TOR activity has been found to extend aging in S. cerevisiae, C. elegans, and D. melanogaster.[31][32][33][34] The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by independent groups at the Jackson Laboratory, University of Texas Health Science Center, and the University of Michigan.[35]

It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.[31][32] But infusion of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.[36]

In a systems biology study by A. Kriete et al. 2010,[37] effects of mTOR inhibition on aging are modeled: According to the free radical theory of aging, reactive oxygen species cause damage of mitochondrial proteins and decrease of 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.[7] Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration.[38] These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates glycolysis[38] and removal of dysfunctional cellular components via autophagy.[37]

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.[39][40][41] 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.[42] In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway, which in turn activates mTOR.[43] Additionally, 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.[44][45] 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.[46][47] These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling.[48]

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.[47][49] 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.[49] Additionally, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed.[49] 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.[49][50][51] 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.[44][52][53][54] It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins.[55]

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.[47][56][57][58][59] 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.[43][60] 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.[61]

Some evidence points to mTOR’s role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy;[62] therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Several groups have proposed that disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD.[63][64][65][66][67][68] Studies using mouse models of Huntington’s disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates.[69][70] Perhaps the same treatment may be useful in clearing Aβ deposits as well.

mTOR inhibitors as therapies

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;[4][71] however, there is as yet no evidence that these substances inhibit mTOR when taken as dietary supplements.

Some (e.g. temsirolimus, everolimus) are beginning to be used in the treatment of cancer.[72][73] mTOR inhibitors may also be useful for treating several age-associated diseases.[74] Ridaforolimus is another mTOR inhibitor, currently in clinical development.

Interactions

Mammalian target of rapamycin has been shown to interact with:[75]

See also

References

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Further reading

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