Адам организміндегі мамырлық протеин (Adam organizmindeǵi mamırlıq protein)

Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), 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. mTOR is a member of the phosphatidylinositol 3 kinase related kinase family of protein kinases. 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. 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. mTORC2 has also been implicated in the control and maintenance of the actin cytoskeleton. However, 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.

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; by David M. Sabatini, Hediye Erdjument Bromage, Mary Lui, Paul Tempst, and Solomon H. Snyder However, the molecular target of the FKBP12 rapamycin complex in mammals was not known. In 1994, researchers working in the labs of Stuart L. Schreiber, Solomon H. Snyder and Robert T. Abraham independently discovered a protein that directly interacts with FKBP12 rapamycin, which became known as mTOR due to its homology to the yeast TOR/DRR genes. Thus, it is used as an immunosuppressant following organ transplantation. Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506 in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit T cell receptor (TCR) and IL 2 receptor signaling pathways, respectively. 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. These studies implicated FKBP12 as a possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade. In 1991, calcineurin was identified as the target of FKBP12 FK506. That of FKBP12 rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12 rapamycin in 1991 and 1993, followed by studies in 1994 when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues. "mTOR" initially meant "mammalian target of rapamycin", but the meaning of the "m" was later changed to "mechanistic". Similarly, with subsequent discoveries the zebra fish TOR was named zTOR, the Arabidopsis thaliana TOR was named AtTOR, and the Drosophila TOR was named dTOR. In 2009 the FRAP1 gene name was officially changed by the HUGO Gene Nomenclature Committee (HGNC) to mTOR, which stands for mechanistic target of rapamycin. 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.

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

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). 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). Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by PDK1 and leads to full Akt activation. 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. 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. Impaired sirtuin 3 leads to mitochondrial dysfunction. 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.

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. RICTOR: Overexpression leads to metastasis and knockdown inhibits growth factor induced PKC phosphorylation. Constitutive deletion of Rictor in mice leads to embryonic lethality, while tissue specific deletion leads to a variety of phenotypes; a common phenotype of Rictor deletion in liver, white adipose tissue, and pancreatic beta cells is systemic glucose intolerance and insulin resistance in one or more tissues. Decreased Rictor expression in mice decreases male, but not female, lifespan. 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. Genetic reduction of mTOR expression in mice significantly increases lifespan. PDK1: Knockout is lethal; hypomorphic allele results in smaller organ volume and organism size but normal AKT activation. AKT: Knockout mice experience spontaneous apoptosis (AKT1), severe diabetes (AKT2), small brains (AKT3), and growth deficiency (AKT1/AKT2). Mice heterozygous for AKT1 have increased lifespan. 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.

Over activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas. Reasons for constitutive activation are 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. Similarly, overexpression of downstream mTOR effectors 4E BP1, S6K1, S6K2 and eIF4E leads to poor cancer prognosis. 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. 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. Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis. 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.

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. mTOR signaling appears to be closely related to the presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively. In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway, which in turn activates mTOR. In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles. Chinese hamster ovary cells transfected with the 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma secretase inhibitor. These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling. Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in the cortex and hippocampus of animal models of AD compared to controls. Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling. 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. It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins. Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients. Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR. Both protein over and under production via mTOR activity seem to contribute to impaired learning and memory. Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity. Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition. Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy; therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD. Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates. Perhaps the same treatment may be useful in clearing Aβ deposits as well.

Hyperactive mTOR pathways have been identified in certain lymphoproliferative diseases such as autoimmune lymphoproliferative syndrome (ALPS), multicentric Castleman disease, and post transplant lymphoproliferative disorder (PTLD).

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. 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. mTORC2 activation appears to mediate neurite outgrowth in differentiated mouse neuro2a cells. 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.

Active mTORC1 is positioned on lysosomes. mTOR is inhibited 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. 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 that removes damaged lysosomes. At this stage another galectin, galectin 3, interacts with TRIM16 to guide selective autophagy of damaged lysosomes. many of them being under negative control of mTOR directly such as the ULK1 ATG13 complex, (ii) ULK1 ATG13 FIP200/RB1CC1 complex associates with the Beclin 1 VPS34 ATG14 via direct interactions between ATG13's HORMA domain and ATG14, (iii) ATG16L1 interacts with WIPI2, which binds to PI3P, the enzymatic product of the class III PI3K Beclin 1 VPS34 ATG14. Thus, mTOR inactivation, initiated through GALTOR Beclin 1) of the autophagy systems listed above and further inactivates mTORC1, 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. may contribute to the execution of lysophagy via autophagic receptors such as p62/SQSTM1, which is recruited during lysophagy, mTOR plays a role in fibrotic diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma. 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.

mTOR inhibitors may be useful for treating/preventing several age associated conditions, including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. 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. 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. 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.