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.
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.
[20] Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506 (later called Tacrolimus) in 1987.
[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.
[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.
mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids.
[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).
[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.
[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.
[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.
[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.
[95] Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis.
[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.
[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.
[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.
[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.
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.
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.
[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.
Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS (glycogen synthase) can be increased in skeletal muscle.
[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.