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{{lowercase|title=mTOR}}
{{Infobox_gene}}
The '''mammalian target of [[sirolimus|rapamycin]]''' ('''mTOR'''), also known as the '''mechanistic target of rapamycin''' and '''FK506-binding protein 12-rapamycin-associated protein 1'''  (FRAP1), is a [[kinase]] that in humans is encoded by the ''MTOR'' [[gene]].<ref name="pmid8008069">{{cite journal | vauthors = Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL | title = A mammalian protein targeted by G1-arresting rapamycin-receptor complex | journal = Nature | volume = 369 | issue = 6483 | pages = 756–8 | date = June 1994 | pmid = 8008069 | doi = 10.1038/369756a0 }}</ref><ref name="pmid7518356"/><ref name="ReferenceA">{{cite journal | vauthors = Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT | title = Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells | journal = The Journal of Biological Chemistry | volume = 270 | issue = 2 | pages = 815–22 | date = January 1995 | pmid = 7822316 | doi=10.1074/jbc.270.2.815}}</ref> mTOR is a member of the [[phosphatidylinositol 3-kinase-related kinase]] family of [[protein kinase]]s.<ref name=Mitra2015>{{cite journal | vauthors = Mitra A, Luna JI, Marusina AI, Merleev A, Kundu-Raychaudhuri S, Fiorentino D, Raychaudhuri SP, Maverakis E | title = Dual mTOR Inhibition Is Required to Prevent TGF-β-Mediated Fibrosis: Implications for Scleroderma | journal = The Journal of Investigative Dermatology | volume = 135 | issue = 11 | pages = 2873–6 | date = November 2015 | pmid = 26134944 | pmc = 4640976 | doi = 10.1038/jid.2015.252 }}</ref>

mTOR links with other proteins and serves as a core component of two distinct [[protein complexes]], [[mTORC1|mTOR complex 1]] and [[mTORC2|mTOR complex 2]], which regulate different cellular processes.<ref name="The neurology of mTOR" /> 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 (genetics)|transcription]].<ref name="The neurology of mTOR" /><ref name=Hay>{{cite journal | vauthors = Hay N, Sonenberg N | title = Upstream and downstream of mTOR | journal = Genes & Development | volume = 18 | issue = 16 | pages = 1926–45 | date = August 2004 | pmid = 15314020 | doi = 10.1101/gad.1212704 }}</ref> As a core component of mTORC2, mTOR also functions as a [[tyrosine protein kinase]] that promotes the activation of [[insulin receptor]]s and [[insulin-like growth factor 1 receptor]]s.<ref name="Yin_2016">{{cite journal | vauthors = Yin Y, Hua H, Li M, Liu S, Kong Q, Shao T, Wang J, Luo Y, Wang Q, Luo T, Jiang Y | title = mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR | journal = Cell Research | volume = 26 | issue = 1 | pages = 46–65 | date = January 2016 | pmid = 26584640 | doi = 10.1038/cr.2015.133 | pmc = 4816127 }}</ref> mTORC2 has also been implicated in the control and maintenance of the [[actin cytoskeleton]].<ref name="The neurology of mTOR" /><ref name="pmid15467718" />

==Discovery==

===Rapa Nui (Easter Island - Chile)===

The study of TOR 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 a soil bacterium ''Streptomyces hygroscopicus'', that he purified and initially reported to possess potent antifungal activity. He appropriately named it rapamycin, noting its original source and activity (Sehgal et al., 1975). However, early testing revealed that rapamycin also had potent immunosuppressive and cytostatic anti-cancer activity. Unfortunately, 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]], and by [[Stuart Schreiber|Stuart L. Schreiber]], [[David M. Sabatini]], and Robert T. Abraham.<ref name="ReferenceB">{{cite journal | vauthors = Heitman J, Movva NR, Hall MN | title = Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast | journal = Science | volume = 253 | issue = 5022 | pages = 905–9 | date = August 1991 | pmid = 1715094 | doi = 10.1126/science.1715094}}</ref><ref name="pmid7518356"/><ref name="ReferenceA"/> In 1993, George Livi and [[Michael N. Hall]] independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes.<ref>{{cite journal | vauthors = Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, and Hall MN | title = Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression | journal = Cell | volume = 73 | issue = 3 | pages= 585–596 | date = May 1993 | pmid = 8387896 | doi = 10.1016/0092-8674(93)90144-F}}</ref><ref>{{cite journal | vauthors =Cafferkey R, Young PR, McLaughlin MM, Bergsma DJ, Koltin Y, Sathe GM, Faucette L, Eng WK, Johnson RK, Livi GP | title = Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity | journal = Mol Cell Biol | volume = 13 | issue = 10 | pages = 6012–23  | date = October 1993 | pmid = 8413204 | doi = 10.1128/MCB.13.10.6012 | pmc=364661}}</ref> However, the molecular target of the FKBP12-rapamycin complex in mammals was not known. In 1994, [[Stuart Schreiber|Stuart L. Schreiber]], [[David M. Sabatini]] 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.<ref name="pmid8008069"/><ref name="pmid7518356"/><ref name="ReferenceA"/>

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]].<ref name="pmid22168436">{{cite journal | vauthors = Magnuson B, Ekim B, Fingar DC | title = Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signaling networks | journal = The Biochemical Journal | volume = 441 | issue = 1 | pages = 1–21 | date = January 2012 | pmid = 22168436 | doi = 10.1042/BJ20110892 }}</ref>  Thus, it is used as an [[immunosuppressant]] following organ transplantation.<ref name="pmid8717522">{{cite journal | vauthors = Abraham RT, Wiederrecht GJ | title = Immunopharmacology of rapamycin | journal = Annual Review of Immunology | volume = 14 | issue =  | pages = 483–510 | year = 1996 | pmid = 8717522 | doi = 10.1146/annurev.immunol.14.1.483 }}</ref>  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.<ref>{{cite journal | vauthors = Bierer BE, Mattila PS, Standaert RF, Herzenberg LA, Burakoff SJ, Crabtree G, Schreiber SL | title = Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 23 | pages = 9231–5 | date = December 1990 | pmid = 2123553 | pmc = 55138 | doi=10.1073/pnas.87.23.9231}}</ref><ref>{{cite journal | vauthors = Bierer BE, Somers PK, Wandless TJ, Burakoff SJ, Schreiber SL | title = Probing immunosuppressant action with a nonnatural immunophilin ligand | journal = Science | volume = 250 | issue = 4980 | pages = 556–9 | date = October 1990 | pmid = 1700475 | doi=10.1126/science.1700475}}</ref>  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.<ref>{{cite journal | vauthors = Dumont FJ, Melino MR, Staruch MJ, Koprak SL, Fischer PA, Sigal NH | title = The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells | journal = J Immunol | volume = 144 | issue = 4 | pages = 1418–24 | date = February 1990 | pmid = 1689353 }}</ref><ref>{{cite journal | vauthors = Dumont FJ, Staruch MJ, Koprak SL, Melino MR, Sigal NH | title = Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin | journal = J Immunol | volume = 144 | issue = 1 | pages = 251–8 | date = January 1990 | pmid = 1688572 }}</ref>  These studies implicated FKBP12 as a possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade.<ref>{{cite journal | vauthors = Harding MW, Galat A, Uehling DE, Schreiber SL | title = A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase | journal = Nature | volume = 341 | issue = 6244 | pages = 758–60 | date = October 1989 | pmid = 2477715 | doi = 10.1038/341758a0 }}</ref><ref>{{cite journal | vauthors = Fretz H, Albers MW, Galat A, Standaert RF, Lane WS, Burakoff SJ, Bierer BE, Schreiber SL | name-list-format = vanc | date = February 1991 | title = Rapamycin and FK506 binding proteins (immunophilins) | journal = Journal of the American Chemical Society | volume = 113 | issue = 4 | pages = 1409–1411 | doi = 10.1021/ja00004a051 }}</ref>

In 1991, [[calcineurin]] was identified as the target of FKBP12-FK506.<ref>{{cite journal | vauthors = Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL | title = Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes | journal = Cell | volume = 66 | issue = 4 | pages = 807–15 | date = August 1991 | pmid = 1715244 | doi=10.1016/0092-8674(91)90124-H}}</ref>  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,<ref name="ReferenceB"/><ref>{{cite journal | vauthors = Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, and Hall MN | title = Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression | journal = Cell |volume= 73 |issue=3 |pages= 585–596 |date= May 1993 |pmid= 8387896 |doi= 10.1016/0092-8674(93)90144-F}}</ref> followed by studies in 1994 when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues.<ref name="pmid8008069" /><ref name="pmid7518356">{{cite journal | vauthors = Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH | title = RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs | journal = Cell | volume = 78 | issue = 1 | pages = 35–43 | date = July 1994 | pmid = 7518356 | doi = 10.1016/0092-8674(94)90570-3 }}</ref><ref name="pmid8717522" />   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;<ref name="pmid8008069" /><ref name="pmid7518356" /> ''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,<ref name="pmid8008069" />  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.<ref>{{cite journal | vauthors = Heitman J  | title = On the discovery of TOR as the target of rapamycin | journal = PLOS Pathogens | volume = 11 | issue = 11 | pages = e1005245 | date = November 2015 | pmid = 26540102 | doi = 10.1371/journal.ppat.1005245 | pmc=4634758}}</ref> 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.

== Function ==
mTOR integrates the input from upstream [[Signal transduction|pathways]], including [[insulin]], [[growth factors]] (such as [[IGF-1]] and [[IGF-2]]), and [[amino acid]]s.<ref name=Hay/> mTOR also senses cellular nutrient, oxygen, and energy levels.<ref name=Tok>{{cite journal | vauthors = Tokunaga C, Yoshino K, Yonezawa K | title = mTOR integrates amino acid- and energy-sensing pathways | journal = Biochemical and Biophysical Research Communications | volume = 313 | issue = 2 | pages = 443–6 | date = January 2004 | pmid = 14684182 | doi = 10.1016/j.bbrc.2003.07.019 }}</ref> 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 (mood)|depression]], and certain [[cancer]]s.<ref name=Beevers>{{cite journal | vauthors = Beevers CS, Li F, Liu L, Huang S | title = Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells | journal = International Journal of Cancer | volume = 119 | issue = 4 | pages = 757–64 | date = August 2006 | pmid = 16550606 | doi = 10.1002/ijc.21932 }}</ref><ref>{{cite journal | vauthors = Kennedy BK, Lamming DW | title = The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging | journal = Cell Metabolism | volume = 23 | issue = 6 | pages = 990–1003 | date = June 2016 | pmid = 27304501 | pmc = 4910876 | doi = 10.1016/j.cmet.2016.05.009 }}</ref> [[Rapamycin]] inhibits mTOR by associating with its intracellular receptor [[FKBP|FKBP12]].<ref name=Huang2001>{{cite journal | vauthors = Huang S, Houghton PJ | title = Mechanisms of resistance to rapamycins | journal = Drug Resistance Updates | volume = 4 | issue = 6 | pages = 378–91 | date = December 2001 | pmid = 12030785 | doi = 10.1054/drup.2002.0227 }}</ref><ref name=Huang2003>{{cite journal | vauthors = Huang S, Bjornsti MA, Houghton PJ | title = Rapamycins: mechanism of action and cellular resistance | journal = Cancer Biology & Therapy | volume = 2 | issue = 3 | pages = 222–32 | year = 2003 | pmid = 12878853 | doi = 10.4161/cbt.2.3.360 }}</ref> The [[FKBP|FKBP12]]–[[rapamycin]] complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.<ref name=Huang2003/>

==Complexes==
[[File:MTOR complexes.png|thumb|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.<ref name="The neurology of mTOR">{{cite journal | vauthors = Lipton JO, Sahin M | title = The neurology of mTOR | journal = Neuron | volume = 84 | issue = 2 | pages = 275–291 | date = October 2014 | pmid = 25374355 | pmc = 4223653 | doi = 10.1016/j.neuron.2014.09.034 | quote = 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.&nbsp;...<br />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.}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223653/figure/F1/ Figure 1: Domain structure of the mTOR kinase and components of mTORC1 and mTORC2]<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223653/figure/F2/ Figure 2: The mTOR Signaling Pathway]</ref>]]
mTOR is the [[catalytic]] subunit of two structurally distinct complexes: mTORC1 and mTORC2.<ref name=Wull>{{cite journal | vauthors = Wullschleger S, Loewith R, Hall MN | title = TOR signaling in growth and metabolism | journal = Cell | volume = 124 | issue = 3 | pages = 471–84 | date = February 2006 | pmid = 16469695 | doi = 10.1016/j.cell.2006.01.016 }}</ref> Both complexes localize to different subcellular compartments, thus affecting their activation and function.<ref name="pmid24385483">{{cite journal | vauthors = Betz C, Hall MN | title = Where is mTOR and what is it doing there? | journal = The Journal of Cell Biology | volume = 203 | issue = 4 | pages = 563–74 | date = November 2013 | pmid = 24385483 | pmc = 3840941 | doi = 10.1083/jcb.201306041 }}</ref> 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.<ref>{{cite journal | vauthors = Groenewoud MJ, Zwartkruis FJ | title = Rheb and Rags come together at the lysosome to activate mTORC1 | journal = Biochemical Society Transactions | volume = 41 | issue = 4 | pages = 951–5 | date = August 2013 | pmid = 23863162 | doi = 10.1042/bst20130037 }}</ref><ref>{{cite journal | vauthors = Efeyan A, Zoncu R, Sabatini DM | title = Amino acids and mTORC1: from lysosomes to disease | journal = Trends in Molecular Medicine | volume = 18 | issue = 9 | pages = 524–33 | date = September 2012 | pmid = 22749019 | pmc = 3432651 | doi = 10.1016/j.molmed.2012.05.007 }}</ref>

===mTORC1===
{{main|mTORC1}}
mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR ([[RPTOR|Raptor]]), mammalian lethal with SEC13 protein 8  ([[mLST8]]) and the non-core components [[AKT1S1|PRAS40]] and [[DEPTOR]].<ref name="pmid12150925">{{cite journal | vauthors = Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM | title = mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery | journal = Cell | volume = 110 | issue = 2 | pages = 163–75 | date = July 2002 | pmid = 12150925 | doi = 10.1016/S0092-8674(02)00808-5 }}</ref><ref name=Kim2003>{{cite journal | vauthors = Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM | title = GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR | journal = Molecular Cell | volume = 11 | issue = 4 | pages = 895–904 | date = April 2003 | pmid = 12718876 | doi = 10.1016/S1097-2765(03)00114-X }}</ref>  This complex functions as a nutrient/energy/redox sensor and controls protein synthesis.<ref name=Hay/><ref name="pmid12150925"/> The activity of mTORC1 is regulated by [[rapamycin]], insulin, growth factors, [[phosphatidic acid]], certain [[amino acids]] and their derivatives (e.g., [[leucine|{{smallcaps all|L}}-leucine]] and [[β-hydroxy β-methylbutyric acid]]), mechanical stimuli, and [[oxidative stress]].<ref name="pmid12150925" /><ref name=Fang>{{cite journal | vauthors = Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J | title = Phosphatidic acid-mediated mitogenic activation of mTOR signaling | journal = Science | volume = 294 | issue = 5548 | pages = 1942–5 | date = November 2001 | pmid = 11729323 | doi = 10.1126/science.1066015 }}</ref><ref name="mTORC1 signaling review">{{cite journal | vauthors = Bond P | title = Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance | journal = J. Int. Soc. Sports Nutr. | volume = 13 | issue = | pages = 8 | date = March 2016 | pmid = 26937223 | pmc = 4774173 | doi = 10.1186/s12970-016-0118-y | quote = }}</ref>

===mTORC2===
{{main|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 ([[MAPKAP1|mSIN1]]).<ref name="pmid16919458">{{cite journal | vauthors = Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM | title = mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s | journal = Current Biology | volume = 16 | issue = 18 | pages = 1865–70 | date = September 2006 | pmid = 16919458 | doi = 10.1016/j.cub.2006.08.001 }}</ref><ref name="pmid15268862">{{cite journal | vauthors = Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM | title = Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton | journal = Current Biology | volume = 14 | issue = 14 | pages = 1296–302 | date = July 2004 | pmid = 15268862 | doi = 10.1016/j.cub.2004.06.054 }}</ref>  mTORC2 has been shown to function as an important regulator of the [[actin cytoskeleton]] through its stimulation of F-[[actin]] stress fibers, [[paxillin]], [[RHOA|RhoA]], [[RAC1|Rac1]], [[CDC42|Cdc42]], and [[protein kinase C]] α ([[PKC alpha|PKCα]]).<ref name="pmid15268862"/>  mTORC2 also phosphorylates the serine/threonine protein kinase [[AKT|Akt/PKB]] on serine residue Ser473, thus affecting metabolism and survival.<ref name="pmid23852728">{{cite journal | vauthors = Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall MN | title = Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 31 | pages = 12526–34 | date = July 2013 | pmid = 23852728 | pmc = 3732980 | doi = 10.1073/pnas.1302455110 }}</ref> Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by [[PDPK1|PDK1]] and leads to full Akt activation.<ref name="pmid15718470">{{cite journal | vauthors = Sarbassov DD, Guertin DA, Ali SM, Sabatini DM | title = Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex | journal = Science | volume = 307 | issue = 5712 | pages = 1098–101 | date = February 2005 | pmid = 15718470 | doi = 10.1126/science.1106148 }}</ref><ref name=Stephens>{{cite journal | vauthors = Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT | title = Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B | journal = Science | volume = 279 | issue = 5351 | pages = 710–4 | date = January 1998 | pmid = 9445477 | doi = 10.1126/science.279.5351.710 }}</ref> In addition, mTORC2 exhibits [[tyrosine protein kinase]] activity and phosphorylates the [[insulin-like growth factor 1 receptor]] (IGF-IR) and [[insulin receptor]] (InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR.<ref name="Yin_2016"/>

=== Inhibition by rapamycin ===
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.<ref name="pmid22461615">{{cite journal | vauthors = Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA | title = Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity | journal = Science | volume = 335 | issue = 6076 | pages = 1638–43 | date = March 2012 | pmid = 22461615 | pmc = 3324089 | doi = 10.1126/science.1215135 }}</ref>

== 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 [[gene knockdown|knockdowns]] and [[gene knockout|knockouts]] and were found to produce the following phenotypes:
* [[NIP7]]: Knockdown reduced mTORC2 activity that is indicated by decreased phosphorylation of mTORC2 substrates.<ref name="Zinzalla">{{cite journal | vauthors = Zinzalla V, Stracka D, Oppliger W, Hall MN | title = Activation of mTORC2 by association with the ribosome | journal = Cell | volume = 144 | issue = 5 | pages = 757–68 | date = March 2011 | pmid = 21376236 | doi = 10.1016/j.cell.2011.02.014 }}</ref>
* [[RICTOR]]: Overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation.<ref name="Zhang">{{cite journal | vauthors = Zhang F, Zhang X, Li M, Chen P, Zhang B, Guo H, Cao W, Wei X, Cao X, Hao X, Zhang N | title = mTOR complex component Rictor interacts with PKCzeta and regulates cancer cell metastasis | journal = Cancer Research | volume = 70 | issue = 22 | pages = 9360–70 | date = November 2010 | pmid = 20978191 | doi = 10.1158/0008-5472.CAN-10-0207 }}</ref> Constitutive deletion of Rictor in mice leads to embryonic lethality,<ref>{{cite journal | vauthors = Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM | title = 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 | journal = Developmental Cell | volume = 11 | issue = 6 | pages = 859–71 | date = December 2006 | pmid = 17141160 | doi = 10.1016/j.devcel.2006.10.007 }}</ref> 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.<ref name="pmid22461615"/><ref>{{cite journal | vauthors = Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA | title = Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size | journal = Diabetes | volume = 60 | issue = 3 | pages = 827–37 | date = March 2011 | pmid = 21266327 | pmc = 3046843 | doi = 10.2337/db10-1194 }}</ref><ref>{{cite journal | vauthors = Lamming DW, Demirkan G, Boylan JM, Mihaylova MM, Peng T, Ferreira J, Neretti N, Salomon A, Sabatini DM, Gruppuso PA | title = Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2) | journal = FASEB Journal | volume = 28 | issue = 1 | pages = 300–15 | date = January 2014 | pmid = 24072782 | pmc = 3868844 | doi = 10.1096/fj.13-237743 }}</ref><ref>{{cite journal | vauthors = Kumar A, Lawrence JC, Jung DY, Ko HJ, Keller SR, Kim JK, Magnuson MA, Harris TE | title = Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism | journal = Diabetes | volume = 59 | issue = 6 | pages = 1397–406 | date = June 2010 | pmid = 20332342 | pmc = 2874700 | doi = 10.2337/db09-1061 }}</ref> Decreased Rictor expression in mice decreases male, but not female, lifespan.<ref>{{cite journal | vauthors = Lamming DW, Mihaylova MM, Katajisto P, Baar EL, Yilmaz OH, Hutchins A, Gultekin Y, Gaither R, Sabatini DM | title = Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan | journal = Aging Cell | volume = 13 | issue = 5 | pages = 911–7 | date = October 2014 | pmid = 25059582 | pmc = 4172536 | doi = 10.1111/acel.12256 }}</ref>
* 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]].<ref name="Feldman">{{cite journal | vauthors = Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM | title = Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 | journal = PLoS Biology | volume = 7 | issue = 2 | pages = e38 | date = February 2009 | pmid = 19209957 | pmc = 2637922 | doi = 10.1371/journal.pbio.1000038 }}</ref> Genetic reduction of mTOR expression in mice significantly increases lifespan.<ref>{{cite journal | vauthors = Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N, Fergusson MM, Rovira II, Allen M, Springer DA, Lago CU, Zhang S, DuBois W, Ward T, deCabo R, Gavrilova O, Mock B, Finkel T | title = Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression | journal = Cell Reports | volume = 4 | issue = 5 | pages = 913–20 | date = September 2013 | pmid = 23994476 | pmc = 3784301 | doi = 10.1016/j.celrep.2013.07.030 }}</ref>
* [[Pyruvate dehydrogenase lipoamide kinase isozyme 1|PDK1]]: Knockout is lethal; [[Muller's morphs|hypomorphic allele]] results in smaller organ volume and organism size but normal AKT activation.<ref name="Lawlor">{{cite journal | vauthors = Lawlor MA, Mora A, Ashby PR, Williams MR, Murray-Tait V, Malone L, Prescott AR, Lucocq JM, Alessi DR | title = Essential role of PDK1 in regulating cell size and development in mice | journal = The EMBO Journal | volume = 21 | issue = 14 | pages = 3728–38 | date = July 2002 | pmid = 12110585 | pmc = 126129 | doi = 10.1093/emboj/cdf387 }}</ref>
* [[AKT]]: Knockout mice experience spontaneous apoptosis ([[AKT1]]), severe diabetes ([[AKT2]]), small brains ([[AKT3]]), and growth deficiency (AKT1/AKT2).<ref name="Yang">{{cite journal | vauthors = Yang ZZ, Tschopp O, Baudry A, Dümmler B, Hynx D, Hemmings BA | title = Physiological functions of protein kinase B/Akt | journal = Biochemical Society Transactions | volume = 32 | issue = Pt 2 | pages = 350–4 | date = April 2004 | pmid = 15046607 | doi = 10.1042/BST0320350 }}</ref> Mice heterozygous for AKT1 have increased lifespan.<ref>{{cite journal | vauthors = Nojima A, Yamashita M, Yoshida Y, Shimizu I, Ichimiya H, Kamimura N, Kobayashi Y, Ohta S, Ishii N, Minamino T | title = Haploinsufficiency of akt1 prolongs the lifespan of mice | journal = PLOS ONE | volume = 8 | issue = 7 | pages = e69178 | date = 2013-01-01 | pmid = 23935948 | pmc = 3728301 | doi = 10.1371/journal.pone.0069178 }}</ref> 
*TOR1, the ''[[Saccharomyces cerevisiae|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.<ref name = "Crespo">{{cite journal | vauthors = Crespo JL, Hall MN | title = Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae | journal = Microbiology and Molecular Biology Reviews | volume = 66 | issue = 4 | pages = 579–91, table of contents | date = December 2002 | pmid = 12456783 | pmc = 134654 | doi = 10.1128/mmbr.66.4.579-591.2002 }}</ref><ref name = "Peter">{{cite journal | vauthors = Peter GJ, Düring L, Ahmed A | title = Carbon catabolite repression regulates amino acid permeases in Saccharomyces cerevisiae via the TOR signaling pathway | journal = The Journal of Biological Chemistry | volume = 281 | issue = 9 | pages = 5546–52 | date = March 2006 | pmid = 16407266 | doi = 10.1074/jbc.M513842200 }}</ref>

== Clinical significance ==

=== Aging ===
[[Image:MTOR-pathway-v1.7.svg|thumb|right|300px|mTOR signaling pathway.[http://www.betz.lu/index.php/2009/01/08/mtor-pathway-2009?blog=6]]]
Decreased TOR activity has been found to increase life span in ''[[Saccharomyces cerevisiae|S. cerevisiae]]'', ''[[Caenorhabditis elegans|C. elegans]],'' and ''[[Drosophila melanogaster|D. melanogaster]]''.<ref name="Powers_2006">{{cite journal | vauthors = Powers RW, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S | title = Extension of chronological life span in yeast by decreased TOR pathway signaling | journal = Genes & Development | volume = 20 | issue = 2 | pages = 174–84 | date = January 2006 | pmid = 16418483 | pmc = 1356109 | doi = 10.1101/gad.1381406 }}</ref><ref name="Kaeberlein_2005">{{cite journal | vauthors = Kaeberlein M, Powers RW, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK | title = Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients | journal = Science | volume = 310 | issue = 5751 | pages = 1193–6 | date = November 2005 | pmid = 16293764 | doi = 10.1126/science.1115535 }}</ref><ref name="pmid15253933">{{cite journal | vauthors = Jia K, Chen D, Riddle DL | title = The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span | journal = Development | volume = 131 | issue = 16 | pages = 3897–906 | date = August 2004 | pmid = 15253933 | doi = 10.1242/dev.01255 }}</ref><ref name="pmid15186745">{{cite journal | vauthors = Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S | title = Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway | journal = Current Biology | volume = 14 | issue = 10 | pages = 885–90 | date = May 2004 | pmid = 15186745 | pmc = 2754830 | doi = 10.1016/j.cub.2004.03.059 }}</ref> The mTOR inhibitor [[rapamycin]] has been confirmed to increase lifespan in mice.<ref name="harrison&strong">{{cite journal | vauthors = Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA | title = Rapamycin fed late in life extends lifespan in genetically heterogeneous mice | journal = Nature | volume = 460 | issue = 7253 | pages = 392–5 | date = July 2009 | pmid = 19587680 | pmc = 2786175 | doi = 10.1038/nature08221 }}</ref><ref>{{cite journal | vauthors = Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R | title = Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction | journal = Aging Cell | volume = 13 | issue = 3 | pages = 468–77 | date = June 2014 | pmid = 24341993 | pmc = 4032600 | doi = 10.1111/acel.12194 }}</ref><ref>{{cite journal | vauthors = Fok WC, Chen Y, Bokov A, Zhang Y, Salmon AB, Diaz V, Javors M, Wood WH, Zhang Y, Becker KG, Pérez VI, Richardson A | title = Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome | journal = PLOS ONE | volume = 9 | issue = 1 | pages = e83988 | date = 2014-01-01 | pmid = 24409289 | pmc = 3883653 | doi = 10.1371/journal.pone.0083988 }}</ref><ref>{{cite journal | vauthors = Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW | title = Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 71 | issue = 7 | pages = 876–81 | date = July 2016 | pmid = 27091134 | pmc = 4906329 | doi = 10.1093/gerona/glw064 }}</ref><ref>{{cite journal | vauthors = Popovich IG, Anisimov VN, Zabezhinski MA, Semenchenko AV, Tyndyk ML, Yurova MN, Blagosklonny MV | title = Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin | journal = Cancer Biology & Therapy | volume = 15 | issue = 5 | pages = 586–92 | date = May 2014 | pmid = 24556924 | pmc = 4026081 | doi = 10.4161/cbt.28164 }}</ref>

It is hypothesized that some dietary regimes, like [[caloric restriction]] and [[methionine]] restriction, cause lifespan extension by decreasing mTOR activity.<ref name="Powers_2006"/><ref name="Kaeberlein_2005"/> 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.<ref>{{cite journal | vauthors = Baar EL, Carbajal KA, Ong IM, Lamming DW | title = Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice | journal = Aging Cell | volume = 15 | issue = 1 | pages = 155–66 | date = February 2016 | pmid = 26695882 | pmc = 4717274 | doi = 10.1111/acel.12425 }}</ref> An alternative theory is mTOR signaling is an example of [[Antagonistic pleiotropy hypothesis|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.<ref>{{cite journal | vauthors = Caron A, Richard D, Laplante M | title = The Roles of mTOR Complexes in Lipid Metabolism | journal = Annual Review of Nutrition | volume = 35 | pages = 321–48 | date = Jul 2015 | pmid = 26185979 | doi = 10.1146/annurev-nutr-071714-034355 }}</ref>  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.<ref>{{cite journal | vauthors = Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ|authorlink7=Randy Seeley | title = Hypothalamic mTOR signaling regulates food intake | journal = Science | volume = 312 | issue = 5775 | pages = 927–30 | date = May 2006 | pmid = 16690869 | doi = 10.1126/science.1124147 }}</ref>

According to the [[free radical theory of aging]],<ref name="kriete2010">{{cite journal | vauthors = Kriete A, Bosl WJ, Booker G | title = Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses | journal = PLoS Computational Biology | volume = 6 | issue = 6 | pages = e1000820 | date = June 2010 | pmid = 20585546 | pmc = 2887462 | doi = 10.1371/journal.pcbi.1000820 }}</ref> [[reactive oxygen species]] cause damage of [[mitochondrial]] proteins and decrease ATP production. Subsequently, via ATP sensitive [[AMP-activated protein kinase|AMPK]], the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the [[ribosome]].<ref name="pmid22168436" /> Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits [[Respiratory chain|mitochondrial respiration]].<ref name="pmid16847060">{{cite journal | vauthors = Schieke SM, Phillips D, McCoy JP, Aponte AM, Shen RF, Balaban RS, Finkel T | title = The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity | journal = The Journal of Biological Chemistry | volume = 281 | issue = 37 | pages = 27643–52 | date = September 2006 | pmid = 16847060 | doi = 10.1074/jbc.M603536200 }}</ref> These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates [[glycolysis]]<ref name="pmid16847060"/> and removal of dysfunctional cellular components via [[autophagy]].<ref name="kriete2010" />

=== 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.<ref>{{cite journal | vauthors = Xu K, Liu P, Wei W | title = mTOR signaling in tumorigenesis | journal = Biochimica et Biophysica Acta | volume = 1846 | issue = 2 | pages = 638–54 | date = December 2014 | pmid = 25450580 | doi = 10.1016/j.bbcan.2014.10.007 | pmc=4261029}}</ref> Reasons for constitutive activation are several. Among the most common are mutations in tumor suppressor [[PTEN (gene)|''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]].<ref>{{cite journal | vauthors = Guertin DA, Sabatini DM | title = An expanding role for mTOR in cancer | journal = Trends in Molecular Medicine | volume = 11 | issue = 8 | pages = 353–61 | date = August 2005 | pmid = 16002336 | doi = 10.1016/j.molmed.2005.06.007 }}</ref> Similarly, overexpression of downstream mTOR effectors [[4E-BP1]], [[S6K]] and [[eIF4E]] leads to poor cancer prognosis.<ref>{{cite journal | vauthors = Pópulo H, Lopes JM, Soares P | title = The mTOR signalling pathway in human cancer | journal = International Journal of Molecular Sciences | volume = 13 | issue = 2 | pages = 1886–918 | date = 2012 | pmid = 22408430 | pmc = 3291999 | doi = 10.3390/ijms13021886 }}</ref> Also, mutations in [[Tuberous sclerosis protein|TSC]] proteins that inhibit the activity of mTOR may lead to a condition named [[Tuberous sclerosis|tuberous sclerosis complex]], which exhibits as benign lesions and increases the risk of [[renal cell carcinoma]].<ref name="pmid17041628">{{cite journal | vauthors = Easton JB, Houghton PJ | title = mTOR and cancer therapy | journal = Oncogene | volume = 25 | issue = 48 | pages = 6436–46 | date = October 2006 | pmid = 17041628 | doi = 10.1038/sj.onc.1209886 }}</ref>

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]].<ref>{{cite journal | vauthors = Zoncu R, Efeyan A, Sabatini DM | title = mTOR: from growth signal integration to cancer, diabetes and ageing | journal = Nature Reviews Molecular Cell Biology | volume = 12 | issue = 1 | pages = 21–35 | date = January 2011 | pmid = 21157483 | pmc = 3390257 | doi = 10.1038/nrm3025 }}</ref> Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of [[HIF1A]] and supporting [[angiogenesis]].<ref>{{cite journal | vauthors = Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL | title = Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer | journal = Nature Medicine | volume = 12 | issue = 1 | pages = 122–7 | date = January 2006 | pmid = 16341243 | doi = 10.1038/nm1337 }}</ref> mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of [[glycolysis|glycolytic metabolism]]. [[Akt2]], a substrate of mTOR, specifically of [[mTORC2]], upregulates expression of the glycolytic enzyme [[PKM2]] thus contributing to the [[Warburg effect (oncology)|Warburg effect]].<ref>{{cite journal | vauthors = Nemazanyy I, Espeillac C, Pende M, Panasyuk G | title = Role of PI3K, mTOR and Akt2 signalling in hepatic tumorigenesis via the control of PKM2 expression | journal = Biochemical Society Transactions | volume = 41 | issue = 4 | pages = 917–22 | date = August 2013 | pmid = 23863156 | doi = 10.1042/BST20130034 }}</ref>

=== Central nervous system disorders / Brain function ===
{{main|Central nervous system disorder}}
{{expand section|<ref name="The neurology of mTOR" />|date=October 2016}}

==== Autism ====
MTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in [[autism spectrum]] disorders.<ref>{{cite journal | vauthors = Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A, Yue Z, Arancio O, Peterson BS, Champagne F, Dwork AJ, Goldman J, Sulzer D | title = Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits | journal = Neuron | volume = 83 | issue = 5 | pages = 1131–43 | date = September 2014 | pmid = 25155956 | doi = 10.1016/j.neuron.2014.07.040 | pmc=4159743}}</ref>

==== 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.<ref name="Rosner M, et al.">{{cite journal | vauthors = Rosner M, Hanneder M, Siegel N, Valli A, Fuchs C, Hengstschläger M | title = The mTOR pathway and its role in human genetic diseases | journal = Mutation Research | volume = 659 | issue = 3 | pages = 284–92 | date = June 2008 | pmid = 18598780 | doi = 10.1016/j.mrrev.2008.06.001 }}</ref><ref name="Li X, et al.">{{cite journal | vauthors = Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ | title = Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain | journal = The FEBS Journal | volume = 272 | issue = 16 | pages = 4211–20 | date = August 2005 | pmid = 16098202 | doi = 10.1111/j.1742-4658.2005.04833.x }}</ref><ref name="Chano, et al.">{{cite journal | vauthors = Chano T, Okabe H, Hulette CM | title = RB1CC1 insufficiency causes neuronal atrophy through mTOR signaling alteration and involved in the pathology of Alzheimer's diseases | journal = Brain Research | volume = 1168 | issue = 1168 | pages = 97–105 | date = September 2007 | pmid = 17706618 | doi = 10.1016/j.brainres.2007.06.075 }}</ref>  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.<ref name="Selkoe">{{cite journal | vauthors = Selkoe DJ | title = Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior | journal = Behavioural Brain Research | volume = 192 | issue = 1 | pages = 106–13 | date = September 2008 | pmid = 18359102 | pmc = 2601528 | doi = 10.1016/j.bbr.2008.02.016 }}</ref>  In vitro studies have shown Aβ to be an activator of the [[PI3K/AKT/mTOR pathway|PI3K/AKT pathway]], which in turn activates mTOR.<ref name="Oddo 2012">{{cite journal | vauthors = Oddo S | title = The role of mTOR signaling in Alzheimer disease | journal = Frontiers in Bioscience | volume = 4 | issue = 1 | pages = 941–52 | date = January 2012 | pmid = 22202101 | pmc = 4111148 | doi = 10.2741/s310 }}</ref>  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.<ref name="An WL, et al.">{{cite journal | vauthors = An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K, Iqbal IG, Winblad B, Pei JJ | title = Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease | journal = The American Journal of Pathology | volume = 163 | issue = 2 | pages = 591–607 | date = August 2003 | pmid = 12875979 | pmc = 1868198 | doi = 10.1016/S0002-9440(10)63687-5 }}</ref><ref name="Zhang 2009">{{cite journal | vauthors = Zhang F, Beharry ZM, Harris TE, Lilly MB, Smith CD, Mahajan S, Kraft AS | title = PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells | journal = Cancer Biology & Therapy | volume = 8 | issue = 9 | pages = 846–53 | date = May 2009 | pmid = 19276681 | doi = 10.4161/cbt.8.9.8210 }}</ref>  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.<ref name="Koo 1994">{{cite journal | vauthors = Koo EH, Squazzo SL | title = Evidence that production and release of amyloid beta-protein involves the endocytic pathway | journal = The Journal of Biological Chemistry | volume = 269 | issue = 26 | pages = 17386–9 | date = July 1994 | pmid = 8021238 }}</ref><ref name="Caccamo 2010">{{cite journal | vauthors = Caccamo A, Majumder S, Richardson A, Strong R, Oddo S | title = Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments | journal = The Journal of Biological Chemistry | volume = 285 | issue = 17 | pages = 13107–20 | date = April 2010 | pmid = 20178983 | pmc = 2857107 | doi = 10.1074/jbc.M110.100420 }}</ref>  These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling.<ref name="Lafay-Chebassier">{{cite journal | vauthors = Lafay-Chebassier C, Paccalin M, Page G, Barc-Pain S, Perault-Pochat MC, Gil R, Pradier L, Hugon J | title = mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease | journal = Journal of Neurochemistry | volume = 94 | issue = 1 | pages = 215–25 | date = July 2005 | pmid = 15953364 | doi = 10.1111/j.1471-4159.2005.03187.x }}</ref>

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.<ref name="Caccamo 2010"/><ref name="Caccamo 2011">{{cite journal | vauthors = Caccamo A, Maldonado MA, Majumder S, Medina DX, Holbein W, Magrí A, Oddo S | title = Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism | journal = The Journal of Biological Chemistry | volume = 286 | issue = 11 | pages = 8924–32 | date = March 2011 | pmid = 21266573 | pmc = 3058958 | doi = 10.1074/jbc.M110.180638 }}</ref>  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.<ref name="Caccamo 2011"/>  In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed.<ref name="Caccamo 2011"/>  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.<ref name="Caccamo 2011"/><ref name="Sancak 2007">{{cite journal | vauthors = Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM | title = PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase | journal = Molecular Cell | volume = 25 | issue = 6 | pages = 903–15 | date = March 2007 | pmid = 17386266 | doi = 10.1016/j.molcel.2007.03.003 }}</ref><ref name="Wang 2007">{{cite journal | vauthors = Wang L, Harris TE, Roth RA, Lawrence JC | title = PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding | journal = The Journal of Biological Chemistry | volume = 282 | issue = 27 | pages = 20036–44 | date = July 2007 | pmid = 17510057 | doi = 10.1074/jbc.M702376200 }}</ref>  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.<ref name="An WL, et al."/><ref name="Pei 2008">{{cite journal | vauthors = Pei JJ, Hugon J | title = mTOR-dependent signalling in Alzheimer's disease | journal = Journal of Cellular and Molecular Medicine | volume = 12 | issue = 6B | pages = 2525–32 | date = December 2008 | pmid = 19210753 | pmc = 3828871 | doi = 10.1111/j.1582-4934.2008.00509.x }}</ref><ref name="Meske 2008">{{cite journal | vauthors = Meske V, Albert F, Ohm TG | title = 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 | journal = The Journal of Biological Chemistry | volume = 283 | issue = 1 | pages = 100–9 | date = January 2008 | pmid = 17971449 | doi = 10.1074/jbc.M704292200 }}</ref><ref name="Janssens 2001">{{cite journal | vauthors = Janssens V, Goris J | title = Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling | journal = The Biochemical Journal | volume = 353 | issue = Pt 3 | pages = 417–39 | date = February 2001 | pmid = 11171037 | pmc = 1221586 | doi = 10.1042/0264-6021:3530417 }}</ref>  It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins.<ref name="Morita 2009">{{cite journal | vauthors = Morita T, Sobue K | title = Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway | journal = The Journal of Biological Chemistry | volume = 284 | issue = 40 | pages = 27734–45 | date = October 2009 | pmid = 19648118 | pmc = 2785701 | doi = 10.1074/jbc.M109.008177 }}</ref>
  
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.<ref name="Caccamo 2010"/><ref name="Puighermanal 2009">{{cite journal | vauthors = Puighermanal E, Marsicano G, Busquets-Garcia A, Lutz B, Maldonado R, Ozaita A | title = Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling | journal = Nature Neuroscience | volume = 12 | issue = 9 | pages = 1152–8 | date = September 2009 | pmid = 19648913 | doi = 10.1038/nn.2369 }}</ref><ref name="Tischmeyer 2003">{{cite journal | vauthors = Tischmeyer W, Schicknick H, Kraus M, Seidenbecher CI, Staak S, Scheich H, Gundelfinger ED | title = Rapamycin-sensitive signalling in long-term consolidation of auditory cortex-dependent memory | journal = The European Journal of Neuroscience | volume = 18 | issue = 4 | pages = 942–50 | date = August 2003 | pmid = 12925020 | doi = 10.1046/j.1460-9568.2003.02820.x }}</ref><ref name="Hoeffer 2010">{{cite journal | vauthors = Hoeffer CA, Klann E | title = mTOR signaling: at the crossroads of plasticity, memory and disease | journal = Trends in Neurosciences | volume = 33 | issue = 2 | pages = 67–75 | date = February 2010 | pmid = 19963289 | pmc = 2821969 | doi = 10.1016/j.tins.2009.11.003 }}</ref><ref name="Kelleher 2004">{{cite journal | vauthors = Kelleher RJ, Govindarajan A, Jung HY, Kang H, Tonegawa S | title = Translational control by MAPK signaling in long-term synaptic plasticity and memory | journal = Cell | volume = 116 | issue = 3 | pages = 467–79 | date = February 2004 | pmid = 15016380 | doi = 10.1016/S0092-8674(04)00115-1 }}</ref>  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.<ref name="Oddo 2012"/><ref name="Ehninger 2008">{{cite journal | vauthors = Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ | title = Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis | journal = Nature Medicine | volume = 14 | issue = 8 | pages = 843–8 | date = August 2008 | pmid = 18568033 | pmc = 2664098 | doi = 10.1038/nm1788 }}</ref>  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.<ref name="Moreno 2012">{{cite journal | vauthors = Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR | title = Sustained translational repression by eIF2α-P mediates prion neurodegeneration | journal = Nature | volume = 485 | issue = 7399 | pages = 507–11 | date = May 2012 | pmid = 22622579 | pmc = 3378208 | doi = 10.1038/nature11058 }}</ref> 
 
Some evidence points to mTOR's role in reduced Aβ clearance as well.  mTOR is a negative regulator of autophagy;<ref name="Diaz-Troya 2008">{{cite journal | vauthors = Díaz-Troya S, Pérez-Pérez ME, Florencio FJ, Crespo JL | title = The role of TOR in autophagy regulation from yeast to plants and mammals | journal = Autophagy | volume = 4 | issue = 7 | pages = 851–65 | date = October 2008 | pmid = 18670193 | doi = 10.4161/auto.6555 }}</ref> 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.<ref name="McCray 2008">{{cite journal | vauthors = McCray BA, Taylor JP | title = The role of autophagy in age-related neurodegeneration | journal = Neuro-Signals | volume = 16 | issue = 1 | pages = 75–84 | date = December 2008 | pmid = 18097162 | doi = 10.1159/000109761 }}</ref><ref name="Nedelsky 2008">{{cite journal | vauthors = Nedelsky NB, Todd PK, Taylor JP | title = Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection | journal = Biochimica et Biophysica Acta | volume = 1782 | issue = 12 | pages = 691–9 | date = December 2008 | pmid = 18930136 | pmc = 2621359 | doi = 10.1016/j.bbadis.2008.10.002 }}</ref><ref name="Rubinsztein, 2006">{{cite journal | vauthors = Rubinsztein DC | title = The roles of intracellular protein-degradation pathways in neurodegeneration | journal = Nature | volume = 443 | issue = 7113 | pages = 780–6 | date = October 2006 | pmid = 17051204 | doi = 10.1038/nature05291 }}</ref><ref name="Oddo 2008">{{cite journal | vauthors = Oddo S | title = The ubiquitin-proteasome system in Alzheimer's disease | journal = Journal of Cellular and Molecular Medicine | volume = 12 | issue = 2 | pages = 363–73 | date = April 2008 | pmid = 18266959 | pmc = 3822529 | doi = 10.1111/j.1582-4934.2008.00276.x }}</ref><ref name="Li 2008">{{cite journal | vauthors = Li X, Li H, Li XJ | title = Intracellular degradation of misfolded proteins in polyglutamine neurodegenerative diseases | journal = Brain Research Reviews | volume = 59 | issue = 1 | pages = 245–52 | date = November 2008 | pmid = 18773920 | pmc = 2577582 | doi = 10.1016/j.brainresrev.2008.08.003 }}</ref><ref name="Caccamo 2009">{{cite journal | vauthors = Caccamo A, Majumder S, Deng JJ, Bai Y, Thornton FB, Oddo S | title = Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability | journal = The Journal of Biological Chemistry | volume = 284 | issue = 40 | pages = 27416–24 | date = October 2009 | pmid = 19651785 | pmc = 2785671 | doi = 10.1074/jbc.M109.031278 }}</ref>  Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates.<ref name="Ravikumar">{{cite journal | vauthors = Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC | title = Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease | journal = Nature Genetics | volume = 36 | issue = 6 | pages = 585–95 | date = June 2004 | pmid = 15146184 | doi = 10.1038/ng1362 }}</ref><ref name="Rami 2009">{{cite journal | vauthors = Rami A | title = Review: autophagy in neurodegeneration: firefighter and/or incendiarist? | journal = Neuropathology and Applied Neurobiology | volume = 35 | issue = 5 | pages = 449–61 | date = October 2009 | pmid = 19555462 | doi = 10.1111/j.1365-2990.2009.01034.x }}</ref>  Perhaps the same treatment may be useful in clearing Aβ deposits as well.

===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.<ref name="Skeletal muscle homeostasis 2016 review" /><ref name="Molecular Aspects of Medicine 2016 review">{{cite journal | vauthors = Brioche T, Pagano AF, Py G, Chopard A | title = Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention | journal = Molecular Aspects of Medicine | volume =  50| issue =  | pages = 56–87 | date = April 2016 | pmid = 27106402 | doi = 10.1016/j.mam.2016.04.006 }}</ref> 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 [[sedentary lifestyle|physical inactivity]].<ref name="Skeletal muscle homeostasis 2016 review" /><ref name="Molecular Aspects of Medicine 2016 review" /><ref name="pmid19150856">{{cite journal | vauthors = Drummond MJ, Dreyer HC, Fry CS, Glynn EL, Rasmussen BB | title = Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling | journal = Journal of Applied Physiology | volume = 106 | issue = 4 | pages = 1374–84 | date = April 2009 | pmid = 19150856 | pmc = 2698645 | doi = 10.1152/japplphysiol.91397.2008 }}</ref> mTORC2 activation appears to mediate [[neurite]] outgrowth in differentiated mouse [[neuro2a cell]]s.<ref name="pmid26267903">{{cite journal | vauthors = Salto R, Vílchez JD, Girón MD, Cabrera E, Campos N, Manzano M, Rueda R, López-Pedrosa JM | title = β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells | journal = PLOS ONE | volume = 10 | issue = 8 | pages = e0135614 | year = 2015 | pmid = 26267903 | pmc = 4534402 | doi = 10.1371/journal.pone.0135614 }}</ref> Intermittent mTOR activation in [[prefrontal cortex|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.<ref name="pmid26973106">{{cite journal | vauthors = Kougias DG, Nolan SO, Koss WA, Kim T, Hankosky ER, Gulley JM, Juraska JM | title = 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 | journal = Neurobiology of Aging | volume = 40 | issue =  | pages = 78–85 | date = April 2016 | pmid = 26973106 | doi = 10.1016/j.neurobiolaging.2016.01.004 }}</ref>

{{multiple image
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 | image1            = Muscle protein synthesis signaling cascades.jpg
 | alt1              = Signaling cascade diagram
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 | caption1          = Diagram of the molecular [[signaling cascade]]s that are involved in [[myofibrillar]] muscle protein synthesis and [[mitochondrial biogenesis]] in response to physical exercise and specific [[amino acid]]s or their derivatives (primarily [[leucine]] and [[Beta-Hydroxy beta-methylbutyric acid|HMB]]).<ref name="Skeletal muscle homeostasis 2016 review">{{cite journal | vauthors = Brook MS, Wilkinson DJ, Phillips BE, Perez-Schindler J, Philp A, Smith K, Atherton PJ | title = Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise | journal = Acta Physiologica | volume = 216 | issue = 1 | pages = 15–41 | date = January 2016 | pmid = 26010896 | pmc = 4843955 | doi = 10.1111/apha.12532 }}</ref> Many amino acids derived from food protein promote the activation of [[mTORC1]] and increase [[protein translation|protein synthesis]] by [[signal transduction|signaling]] through [[Rag GTPase]]s.<ref name="The neurology of mTOR" /><ref name="Skeletal muscle homeostasis 2016 review" /><br />{{hidden|Abbreviations and representations:|{{bull}}PLD: [[phospholipase D]]<br />{{bull}}PA: [[phosphatidic acid]]<br />{{bull}}mTOR: mechanistic target of rapamycin<br />{{bull}}AMP: [[adenosine monophosphate]]<br />{{bull}}ATP: [[adenosine triphosphate]]<br />{{bull}}AMPK: [[AMP-activated protein kinase]]<br />{{bull}}PGC‐1α: [[PGC-1α|peroxisome proliferator-activated receptor gamma coactivator-1α]]<br />{{bull}}S6K1: [[p70S6 kinase]]<br />{{bull}}4EBP1: [[EIF4EBP1|eukaryotic translation initiation factor 4E-binding protein 1]]<br />{{bull}}eIF4E: [[eukaryotic translation initiation factor 4E]]<br />{{bull}}RPS6: [[ribosomal protein S6]]<br />{{bull}}eEF2: [[eukaryotic elongation factor 2]]<br />{{bull}}RE: [[resistance exercise]]; EE: [[endurance exercise]]<br />{{bull}}Myo: [[myofibrillar]]; Mito: [[mitochondria]]l<br />{{bull}}AA: [[amino acids]]<br />{{bull}}HMB: [[β-hydroxy β-methylbutyric acid]]<br />{{bull}}↑ represents activation<br />{{bull}}Τ represents inhibition | headerstyle=background:#ccccff | style=text-align:center; }}
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 | image2            = Resistance exercise-induced muscle protein synthesis.jpg
 | alt2              = Graph of muscle protein synthesis vs time
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 | caption2          = [[Strength training|Resistance training]] stimulates muscle protein synthesis (MPS) for a period of up to 48&nbsp;hours following exercise (shown by dotted line).<ref name="Muscle hypertrophy review" /> 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).<ref name="Muscle hypertrophy review">{{cite journal | vauthors = Phillips SM | title = A brief review of critical processes in exercise-induced muscular hypertrophy | journal = Sports Med. | volume = 44 Suppl 1 | issue = | pages = S71–S77 | date = May 2014 | pmid = 24791918 | pmc = 4008813 | doi = 10.1007/s40279-014-0152-3 | quote = }}</ref>
}}

=== Lysosomal damage inhibits mTOR and induces autophagy ===
Active [[MTORC1|mTOR]]C1 is positioned on [[lysosome]]s.  [[MTORC1|mTOR]] is inhibited <ref name=":0">{{cite journal | vauthors = Jia J, Abudu YP, Claude-Taupin A, Gu Y, Kumar S, Choi SW, Peters R, Mudd MH, Allers L, Salemi M, Phinney B, Johansen T, Deretic V | title = Galectins Control mTOR in Response to Endomembrane Damage | journal = Molecular Cell | volume = 70 | issue = 1 | pages = 120–135.e8 | date = April 2018 | pmid = 29625033 | pmc = 5911935 | doi = 10.1016/j.molcel.2018.03.009 }}</ref> when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading [[Bacterial taxonomy|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 [[Cytoplasmic inclusion|inclusions]] including [[Urate crystal arthropathy|urate]] crystals and [[crystalline silica]].<ref name=":0" /> The process of mTOR inactivation following lysosomal/endomembrane is mediated by the protein complex termed GALTOR.<ref name=":0" /> At the heart of GALTOR<ref name=":0" /> is [[galectin-8]], a member of β-galactoside binding superfamily of cytosolic lectins termed [[galectin]]s, which recognizes lysosomal membrane damage by binding to the exposed [[glycan]]s 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-Rag complex|Ragulator]]'s (LAMTOR1-5 complex) [[Guanine nucleotide exchange factor|guanine nucleotide exchange]] function-<ref name=":0" />  [[Target of rapamycin|TOR]] is a negative regulator of autophagy in general, best studied during response to starvation,<ref>{{cite journal | vauthors = Noda T, Ohsumi Y | title = Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast | journal = The Journal of Biological Chemistry | volume = 273 | issue = 7 | pages = 3963–6 | date = February 1998 | pmid = 9461583 | doi = 10.1074/jbc.273.7.3963  }}</ref><ref>{{cite journal | vauthors = Dubouloz F, Deloche O, Wanke V, Cameroni E, De Virgilio C | title = The TOR and EGO protein complexes orchestrate microautophagy in yeast | journal = Molecular Cell | volume = 19 | issue = 1 | pages = 15–26 | date = July 2005 | pmid = 15989961 | doi = 10.1016/j.molcel.2005.05.020 }}</ref><ref name=":2">{{cite journal | vauthors = Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X | title = ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy | journal = The Journal of Biological Chemistry | volume = 284 | issue = 18 | pages = 12297–305 | date = May 2009 | pmid = 19258318 | pmc = 2673298 | doi = 10.1074/jbc.M900573200 }}</ref><ref name=":3">{{cite journal | vauthors = Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH | title = ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery | journal = Molecular Biology of the Cell | volume = 20 | issue = 7 | pages = 1992–2003 | date = April 2009 | pmid = 19225151 | pmc = 2663920 | doi = 10.1091/mbc.e08-12-1249 }}</ref><ref name=":4">{{cite journal | vauthors = Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N | title = Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy | journal = Molecular Biology of the Cell | volume = 20 | issue = 7 | pages = 1981–91 | date = April 2009 | pmid = 19211835 | pmc = 2663915 | doi = 10.1091/mbc.e08-12-1248 }}</ref> 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<ref>{{cite journal | vauthors = Hasegawa J, Maejima I, Iwamoto R, Yoshimori T | title = Selective autophagy: lysophagy | journal = Methods | volume = 75 | pages = 128–32 | date = March 2015 | pmid = 25542097 | doi = 10.1016/j.ymeth.2014.12.014 }}</ref> that removes damaged lysosomes. At this stage another [[galectin]], [[galectin-3]], interacts with [[TRIM16]] to guide selective autophagy of damaged lysosomes.<ref>{{cite journal | vauthors = Fraiberg M, Elazar Z | title = A TRIM16-Galactin3 Complex Mediates Autophagy of Damaged Endomembranes | journal = Developmental Cell | volume = 39 | issue = 1 | pages = 1–2 | date = October 2016 | pmid = 27728777 | doi = 10.1016/j.devcel.2016.09.025 }}</ref><ref name=":1" /> [[TRIM16]] gathers [[ULK1]] and principal components [[BECN1|(Beclin 1]] and [[ATG16L1]]) of other complexes ([[BECN1|Beclin 1]]-[[Class III PI 3-kinase|VPS34]]-[[ALG14|ATG14]] and [[ATG16L1]]-[[ATG5]]-[[ATG12]]) initiating [[autophagy]],<ref name=":1">{{cite journal | vauthors = Chauhan S, Kumar S, Jain A, Ponpuak M, Mudd MH, Kimura T, Choi SW, Peters R, Mandell M, Bruun JA, Johansen T, Deretic V | title = TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis | journal = Developmental Cell | volume = 39 | issue = 1 | pages = 13–27 | date = October 2016 | pmid = 27693506 | pmc = 5104201 | doi = 10.1016/j.devcel.2016.08.003 }}</ref> many of them being under negative control of mTOR directly such as the ULK1-ATG13 complex,<ref name=":2" /><ref name=":3" /><ref name=":4" /> or indirectly, such as components of t[[Class III PI 3-kinase|he 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]]-[[Autophagy-related protein 13|ATG13]]-[[RB1CC1|FIP200/RB1CC1]] complex associates with the [[MAP1LC3B|LC3B]]/[[GABARAP]] conjugation machinery through direct interactions between [[RB1CC1|FIP200/RB1CC1]] and [[ATG16L1]],<ref>{{cite journal | vauthors = Nishimura T, Kaizuka T, Cadwell K, Sahani MH, Saitoh T, Akira S, Virgin HW, Mizushima N | title = FIP200 regulates targeting of Atg16L1 to the isolation membrane | journal = EMBO Reports | volume = 14 | issue = 3 | pages = 284–91 | date = March 2013 | pmid = 23392225 | pmc = 3589088 | doi = 10.1038/embor.2013.6 }}</ref><ref>{{cite journal | vauthors = Gammoh N, Florey O, Overholtzer M, Jiang X | title = Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy | journal = Nature Structural & Molecular Biology | volume = 20 | issue = 2 | pages = 144–9 | date = February 2013 | pmid = 23262492 | pmc = 3565010 | doi = 10.1038/nsmb.2475 }}</ref><ref name=":5">{{cite journal | vauthors = Fujita N, Morita E, Itoh T, Tanaka A, Nakaoka M, Osada Y, Umemoto T, Saitoh T, Nakatogawa H, Kobayashi S, Haraguchi T, Guan JL, Iwai K, Tokunaga F, Saito K, Ishibashi K, Akira S, Fukuda M, Noda T, Yoshimori T | title = Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin | journal = The Journal of Cell Biology | volume = 203 | issue = 1 | pages = 115–28 | date = October 2013 | pmid = 24100292 | pmc = 3798248 | doi = 10.1083/jcb.201304188 }}</ref> (ii) [[ULK1]]-[[Autophagy-related protein 13|ATG13]]-[[RB1CC1|FIP200/RB1CC1]] complex associates with the [[BECN1|Beclin 1]]-[[Class III PI 3-kinase|VPS34]]-[[ALG14|ATG14]] via direct interactions between [[Autophagy-related protein 13|ATG13]]'s [[HORMA domain|HORMA]] domain and [[ALG14|ATG14]],<ref>{{cite journal | vauthors = Park JM, Jung CH, Seo M, Otto NM, Grunwald D, Kim KH, Moriarity B, Kim YM, Starker C, Nho RS, Voytas D, Kim DH | title = The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14 | journal = Autophagy | volume = 12 | issue = 3 | pages = 547–64 | date = 2016-03-03 | pmid = 27046250 | pmc = 4835982 | doi = 10.1080/15548627.2016.1140293  }}</ref> (iii) [[ATG16L1]] interacts with [[WIPI2]], which binds to [[Phosphatidylinositol 3-phosphate|PI3P]], the enzymatic product of  the class III PI3K [[BECN1|Beclin 1]]-[[Class III PI 3-kinase|VPS34]]-[[ALG14|ATG14]].<ref>{{cite journal | vauthors = Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA | title = WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1 | journal = Molecular Cell | volume = 55 | issue = 2 | pages = 238–52 | date = July 2014 | pmid = 24954904 | pmc = 4104028 | doi = 10.1016/j.molcel.2014.05.021 }}</ref> Thus, mTOR inactivation, initiated through GALTOR<ref name=":0" /> upon lysosomal damage, plus a simultaneous activation via [[galectin-9]] (which also recognizes lysosomal membrane breach) of [[PRKAA1|AMPK]] <ref name=":0" /> that directly phosphorylates and activates key components ([[ULK1]],<ref>{{cite journal | vauthors = Kim J, Kundu M, Viollet B, Guan KL | title = AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 | journal = Nature Cell Biology | volume = 13 | issue = 2 | pages = 132–41 | date = February 2011 | pmid = 21258367 | pmc = 3987946 | doi = 10.1038/ncb2152 }}</ref> [[BECN1|Beclin 1]]<ref>{{cite journal | vauthors = Kim J, Kim YC, Fang C, Russell RC, Kim JH, Fan W, Liu R, Zhong Q, Guan KL | title = Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy | journal = Cell | volume = 152 | issue = 1-2 | pages = 290–303 | date = January 2013 | pmid = 23332761 | pmc = 3587159 | doi = 10.1016/j.cell.2012.12.016 }}</ref>) of the autophagy systems listed above and further inactivates mTORC1,<ref>{{cite journal | vauthors = Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ | title = AMPK phosphorylation of raptor mediates a metabolic checkpoint | journal = Molecular Cell | volume = 30 | issue = 2 | pages = 214–26 | date = April 2008 | pmid = 18439900 | pmc = 2674027 | doi = 10.1016/j.molcel.2008.03.003 }}</ref><ref>{{cite journal | vauthors = Inoki K, Zhu T, Guan KL | title = TSC2 mediates cellular energy response to control cell growth and survival | journal = Cell | volume = 115 | issue = 5 | pages = 577–90 | date = November 2003 | pmid = 14651849 }}</ref> 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.<ref name=":1" /> [[ATG16L1]]  has an intrinsic binding affinity for [[ubiquitin]]<ref name=":5" />); whereas ubiqutination by a glycioprotein-specific FBXO27-endowed ubiquitin ligase of several damage-exposed glycosylated lysosomal membrane proteins such as [[LAMP1]], [[LAMP2]], GNS/[[N-acetylglucosamine-6-sulfatase]], TSPAN6/[[TSPAN6|tetraspanin-6]], PSAP/[[prosaposin]], and TMEM192/transmembrane protein 192 <ref>{{cite journal | vauthors = Yoshida Y, Yasuda S, Fujita T, Hamasaki M, Murakami A, Kawawaki J, Iwai K, Saeki Y, Yoshimori T, Matsuda N, Tanaka K | title = FBXO27 directs damaged lysosomes for autophagy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 32 | pages = 8574–8579 | date = August 2017 | pmid = 28743755 | pmc = 5559013 | doi = 10.1073/pnas.1702615114 }}</ref> may contribute to the execution of lysophagy via autophagic receptors such as p62/[[Sequestosome 1|SQSTM1]], which is recruited during lysophagy,<ref name=":5" /> or other to be determined functions.

===Scleroderma===
[[Scleroderma]], also known as systemic [[Sclerosis (medicine)|sclerosis]], is a chronic [[systemic autoimmune disease]] characterised by hardening (''sclero'') of the skin (''derma'') that affects internal organs in its more severe forms.<ref name = MSR>{{cite web|title=Scleroderma|work=Medscape Reference|publisher=WebMD|accessdate=5 March 2014|date=15 February 2012|url=http://emedicine.medscape.com/article/331864-overview#showall| vauthors = Jimenez SA, Cronin PM, Koenig AS, O'Brien MS, Castro SV | veditors = Varga J, Talavera F, Goldberg E, Mechaber AJ, Diamond HS }}</ref><ref name = MM>{{cite web|title=Systemic Sclerosis|work=Merck Manual Professional|publisher=Merck Sharp & Dohme Corp.|date=June 2013|accessdate=5 March 2014 |url= http://www.merckmanuals.com/professional/musculoskeletal_and_connective_tissue_disorders/autoimmune_rheumatic_disorders/systemic_sclerosis.html | vauthors = Hajj-ali RA}}</ref> mTOR plays a role in [[fibrosis|fibrotic]] diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma.<ref name=Mitra2015/>

== mTOR inhibitors as therapies ==
{{main|mTOR inhibitors}}

===Transplantation===
mTOR inhibitors, e.g. [[rapamycin]], are already used to prevent [[transplant rejection]]. Rapamycin is also related to the therapy of [[glycogen storage disease]] (GSD).

===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 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.<ref name=Beevers/><ref name="pmid20812900">{{cite journal | vauthors = Zhou H, Luo Y, Huang S | title = Updates of mTOR inhibitors | journal = Anti-Cancer Agents in Medicinal Chemistry | volume = 10 | issue = 7 | pages = 571–81 | date = September 2010 | pmid = 20812900 | pmc = 2980558 | doi =  10.2174/187152010793498663}}</ref> As yet no evidence exists that these substances inhibit mTOR signaling when taken as [[dietary supplements]]. However, a natural substance [[Berberine#Research|Berberine]] is available as a dietary supplement. In live cells it localizes in mitochondria, inhibits complex I of respiratory chain thereby decreasing ATP (increasing AMP/ATP ratio) which leads to activation of AMPK and suppression of mTOR signaling, consistent with its potential anti-aging properties.<ref>Zhao H, Halicka HD, Li J, Darzynkiewicz Z. Berberine suppresses gero-conversion from cell cycle arrest to senescence. Aging (Albany) 2013; 6: 623–636. {{PMID|23974852}}, doi:10.18632/aging.100593</ref>

===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).<ref>{{Cite news|url=https://www.pharmaceutical-journal.com/research/review-article/mammalian-target-of-rapamycin-mtor-inhibitors-in-solid-tumours/20200813.article|title=Mammalian target of rapamycin (mTOR) inhibitors in solid tumours|work=Pharmaceutical Journal|access-date=2018-10-18|language=en}}</ref> The complete mechanism of these agents is not clear, but they are thought to function by imparing tumour [[angiogenesis]] and causing impariment of the [[G1/S transition]].<ref>{{cite journal | vauthors = Faivre S, Kroemer G, Raymond E | title = Current development of mTOR inhibitors as anticancer agents | language = En | journal = Nature Reviews. Drug Discovery | volume = 5 | issue = 8 | pages = 671–88 | date = August 2006 | pmid = 16883305 | doi = 10.1038/nrd2062 }}</ref>

===Anti-ageing===
mTOR inhibitors may be useful for treating/preventing several age-associated conditions,<ref name="pmid19805415">{{cite journal | vauthors = Hasty P | title = Rapamycin: the cure for all that ails | journal = Journal of Molecular Cell Biology | volume = 2 | issue = 1 | pages = 17–9 | date = February 2010 | pmid = 19805415 | doi = 10.1093/jmcb/mjp033 }}</ref> including neurodegenerative diseases such as [[Alzheimer's disease]] and [[Parkinson's disease]].<ref name="pmid21772323">{{cite journal | vauthors = Bové J, Martínez-Vicente M, Vila M | title = Fighting neurodegeneration with rapamycin: mechanistic insights | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 8 | pages = 437–52 | date = August 2011 | pmid = 21772323 | doi = 10.1038/nrn3068 }}</ref> After a short-term treatment with mTor inhibitors, in elderly (65 and older), treated subjects had a reduced number of infections, over the course of a year.<ref name="SciTranslMed.">{{cite journal | vauthors = Mannick JB, Morris M, Hockey HP, Roma G, Beibel M, Kulmatycki K, Watkins M, Shavlakadze T, Zhou W, Quinn D, Glass DJ, Klickstein LB | title = TORC1 inhibition enhances immune function and reduces infections in the elderly | journal = Science Translational Medicine | volume = 10 | issue = 449 | pages = eaaq1564 | date = July 2018 | pmid = 29997249 | doi = 10.1126/scitranslmed.aaq1564 }}</ref>

== Interactions ==
Mechanistic target of rapamycin has been shown to [[Protein-protein interaction|interact]] with:<ref name=HPRD>{{cite web | url = http://www.hprd.org/interactions?hprd_id=03134&isoform_id=03134_1&isoform_name= | title = mTOR protein interactors | work = [[Human Protein Reference Database]] | publisher = Johns Hopkins University and the Institute of Bioinformatics | accessdate = 2010-12-06 }}</ref>
{{div col|colwidth=30em}}
* [[ABL1]],<ref name="pmid10753870">{{cite journal | vauthors = Kumar V, Sabatini D, Pandey P, Gingras AC, Majumder PK, Kumar M, Yuan ZM, Carmichael G, Weichselbaum R, Sonenberg N, Kufe D, Kharbanda S | title = 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 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 15 | pages = 10779–87 | date = April 2000 | pmid = 10753870 | doi = 10.1074/jbc.275.15.10779 }}</ref>
* [[AKT1]],<ref name="pmid15718470"/><ref name="pmid10910062">{{cite journal | vauthors = Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT | title = A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells | journal = Cancer Research | volume = 60 | issue = 13 | pages = 3504–13 | date = July 2000 | pmid = 10910062 | doi =  }}</ref><ref name="pmid14970221">{{cite journal | vauthors = Cheng SW, Fryer LG, Carling D, Shepherd PR | title = Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status | journal = The Journal of Biological Chemistry | volume = 279 | issue = 16 | pages = 15719–22 | date = April 2004 | pmid = 14970221 | doi = 10.1074/jbc.C300534200 }}</ref>
* [[IGF-IR]],<ref name="Yin_2016"/>
* [[InsR]],<ref name="Yin_2016"/>
* [[CLIP1]],<ref name="pmid12231510">{{cite journal | vauthors = Choi JH, Bertram PG, Drenan R, Carvalho J, Zhou HH, Zheng XF | title = The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase | journal = EMBO Reports | volume = 3 | issue = 10 | pages = 988–94 | date = October 2002 | pmid = 12231510 | pmc = 1307618 | doi = 10.1093/embo-reports/kvf197 }}</ref>
* [[EIF3F]]<ref name="pmid16541103">{{cite journal | vauthors = Harris TE, Chi A, Shabanowitz J, Hunt DF, Rhoads RE, Lawrence JC | title = mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin | journal = The EMBO Journal | volume = 25 | issue = 8 | pages = 1659–68 | date = April 2006 | pmid = 16541103 | pmc = 1440840 | doi = 10.1038/sj.emboj.7601047 }}</ref>
* [[EIF4EBP1]],<ref name=pmid12150925/><ref name=pmid12747827/><ref name=pmid12150926/><ref name=pmid16798736/><ref name="pmid15854902">{{cite journal | vauthors = Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J | title = Rheb binds and regulates the mTOR kinase | journal = Current Biology | volume = 15 | issue = 8 | pages = 702–13 | date = April 2005 | pmid = 15854902 | doi = 10.1016/j.cub.2005.02.053 }}</ref><ref name="pmid10971657">{{cite journal | vauthors = Takahashi T, Hara K, Inoue H, Kawa Y, Tokunaga C, Hidayat S, Yoshino K, Kuroda Y, Yonezawa K | title = Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and in vitro | journal = Genes to Cells | volume = 5 | issue = 9 | pages = 765–75 | date = September 2000 | pmid = 10971657 | doi = 10.1046/j.1365-2443.2000.00365.x }}</ref><ref name="pmid9465032">{{cite journal | vauthors = Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM | title = RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 4 | pages = 1432–7 | date = February 1998 | pmid = 9465032 | pmc = 19032 | doi = 10.1073/pnas.95.4.1432 }}</ref><ref name="pmid15767663">{{cite journal | vauthors = Wang X, Beugnet A, Murakami M, Yamanaka S, Proud CG | title = Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins | journal = Molecular and Cellular Biology | volume = 25 | issue = 7 | pages = 2558–72 | date = April 2005 | pmid = 15767663 | pmc = 1061630 | doi = 10.1128/MCB.25.7.2558-2572.2005 }}</ref>
* [[FKBP1A]],<ref name="pmid15467718">{{cite journal | vauthors = Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN | title = Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive | journal = Nature Cell Biology | volume = 6 | issue = 11 | pages = 1122–8 | date = November 2004 | pmid = 15467718 | doi = 10.1038/ncb1183 }}</ref><ref name="pmid15268862"/><ref name="pmid8662507">{{cite journal | vauthors = Choi J, Chen J, Schreiber SL, Clardy J | title = Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP | journal = Science | volume = 273 | issue = 5272 | pages = 239–42 | date = July 1996 | pmid = 8662507 | doi = 10.1126/science.273.5272.239 }}</ref><ref name="pmid15284440">{{cite journal | vauthors = Luker KE, Smith MC, Luker GD, Gammon ST, Piwnica-Worms H, Piwnica-Worms D | title = Kinetics of regulated protein-protein interactions revealed with firefly luciferase complementation imaging in cells and living animals | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12288–93 | date = August 2004 | pmid = 15284440 | pmc = 514471 | doi = 10.1073/pnas.0404041101 }}</ref><ref name="pmid15796538">{{cite journal | vauthors = Banaszynski LA, Liu CW, Wandless TJ | title = Characterization of the FKBP.rapamycin.FRB ternary complex | journal = Journal of the American Chemical Society | volume = 127 | issue = 13 | pages = 4715–21 | date = April 2005 | pmid = 15796538 | doi = 10.1021/ja043277y }}</ref><ref name="pmid7822316">{{cite journal | vauthors = Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT | title = Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells | journal = The Journal of Biological Chemistry | volume = 270 | issue = 2 | pages = 815–22 | date = January 1995 | pmid = 7822316 | doi = 10.1074/jbc.270.2.815 }}</ref>
* [[GPHN]],<ref name="pmid10325225">{{cite journal | vauthors = Sabatini DM, Barrow RK, Blackshaw S, Burnett PE, Lai MM, Field ME, Bahr BA, Kirsch J, Betz H, Snyder SH | title = Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling | journal = Science | volume = 284 | issue = 5417 | pages = 1161–4 | date = May 1999 | pmid = 10325225 | doi = 10.1126/science.284.5417.1161 }}</ref>
* [[KIAA1303]],<ref name=pmid15467718/><ref name="pmid12150925"/><ref name="pmid16919458"/><ref name=pmid15268862/><ref name="pmid16847060"/><ref name="pmid12747827">{{cite journal | vauthors = Schalm SS, Fingar DC, Sabatini DM, Blenis J | title = TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function | journal = Current Biology | volume = 13 | issue = 10 | pages = 797–806 | date = May 2003 | pmid = 12747827 | doi = 10.1016/S0960-9822(03)00329-4 }}</ref><ref name="pmid12150926">{{cite journal | vauthors = Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K | title = Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action | journal = Cell | volume = 110 | issue = 2 | pages = 177–89 | date = July 2002 | pmid = 12150926 | doi = 10.1016/S0092-8674(02)00833-4 }}</ref><ref name="pmid16798736">{{cite journal | vauthors = Wang L, Rhodes CJ, Lawrence JC | title = Activation of mammalian target of rapamycin (mTOR) by insulin is associated with stimulation of 4EBP1 binding to dimeric mTOR complex 1 | journal = The Journal of Biological Chemistry | volume = 281 | issue = 34 | pages = 24293–303 | date = August 2006 | pmid = 16798736 | doi = 10.1074/jbc.M603566200 }}</ref><ref name="pmid16837165">{{cite journal | vauthors = Ha SH, Kim DH, Kim IS, Kim JH, Lee MN, Lee HJ, Kim JH, Jang SK, Suh PG, Ryu SH | title = PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals | journal = Cellular Signalling | volume = 18 | issue = 12 | pages = 2283–91 | date = December 2006 | pmid = 16837165 | doi = 10.1016/j.cellsig.2006.05.021 }}</ref><ref name="pmid16631613">{{cite journal | vauthors = Buerger C, DeVries B, Stambolic V | title = Localization of Rheb to the endomembrane is critical for its signaling function | journal = Biochemical and Biophysical Research Communications | volume = 344 | issue = 3 | pages = 869–80 | date = June 2006 | pmid = 16631613 | doi = 10.1016/j.bbrc.2006.03.220 }}</ref><ref name="pmid16962653">{{cite journal | vauthors = Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B | title = SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity | journal = Cell | volume = 127 | issue = 1 | pages = 125–37 | date = October 2006 | pmid = 16962653 | doi = 10.1016/j.cell.2006.08.033 }}</ref><ref name="pmid15459249">{{cite journal | vauthors = McMahon LP, Yue W, Santen RJ, Lawrence JC | title = Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex | journal = Molecular Endocrinology | volume = 19 | issue = 1 | pages = 175–83 | date = January 2005 | pmid = 15459249 | doi = 10.1210/me.2004-0305 }}</ref><ref name="pmid15066126">{{cite journal | vauthors = Oshiro N, Yoshino K, Hidayat S, Tokunaga C, Hara K, Eguchi S, Avruch J, Yonezawa K | title = Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function | journal = Genes to Cells | volume = 9 | issue = 4 | pages = 359–66 | date = April 2004 | pmid = 15066126 | doi = 10.1111/j.1356-9597.2004.00727.x }}</ref><ref name="pmid12719976">{{cite journal | vauthors = Kawai S, Enzan H, Hayashi Y, Jin YL, Guo LM, Miyazaki E, Toi M, Kuroda N, Hiroi M, Saibara T, Nakayama H | title = Vinculin: a novel marker for quiescent and activated hepatic stellate cells in human and rat livers | journal = Virchows Archiv | volume = 443 | issue = 1 | pages = 78–86 | date = July 2003 | pmid = 12719976 | doi = 10.1007/s00428-003-0804-4 }}</ref><ref name="pmid12665511">{{cite journal | vauthors = Choi KM, McMahon LP, Lawrence JC | title = Two motifs in the translational repressor PHAS-I required for efficient phosphorylation by mammalian target of rapamycin and for recognition by raptor | journal = The Journal of Biological Chemistry | volume = 278 | issue = 22 | pages = 19667–73 | date = May 2003 | pmid = 12665511 | doi = 10.1074/jbc.M301142200 }}</ref><ref name="pmid12604610">{{cite journal | vauthors = Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K | title = The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif | journal = The Journal of Biological Chemistry | volume = 278 | issue = 18 | pages = 15461–4 | date = May 2003 | pmid = 12604610 | doi = 10.1074/jbc.C200665200 }}</ref><ref name="pmid16603397">{{cite journal | vauthors = Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM | title = Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB | journal = Molecular Cell | volume = 22 | issue = 2 | pages = 159–68 | date = April 2006 | pmid = 16603397 | doi = 10.1016/j.molcel.2006.03.029 }}</ref><ref name="pmid16354680">{{cite journal | vauthors = Tzatsos A, Kandror KV | title = Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation | journal = Molecular and Cellular Biology | volume = 26 | issue = 1 | pages = 63–76 | date = January 2006 | pmid = 16354680 | pmc = 1317643 | doi = 10.1128/MCB.26.1.63-76.2006 }}</ref><ref name="pmid16183647">{{cite journal | vauthors = Sarbassov DD, Sabatini DM | title = Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex | journal = The Journal of Biological Chemistry | volume = 280 | issue = 47 | pages = 39505–9 | date = November 2005 | pmid = 16183647 | doi = 10.1074/jbc.M506096200 }}</ref><ref name="pmid17043309">{{cite journal | vauthors = Yang Q, Inoki K, Ikenoue T, Guan KL | title = Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity | journal = Genes & Development | volume = 20 | issue = 20 | pages = 2820–32 | date = October 2006 | pmid = 17043309 | pmc = 1619946 | doi = 10.1101/gad.1461206 }}</ref>
* [[PRKCD]],<ref name="pmid10698949">{{cite journal | vauthors = Kumar V, Pandey P, Sabatini D, Kumar M, Majumder PK, Bharti A, Carmichael G, Kufe D, Kharbanda S | title = Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation | journal = The EMBO Journal | volume = 19 | issue = 5 | pages = 1087–97 | date = March 2000 | pmid = 10698949 | pmc = 305647 | doi = 10.1093/emboj/19.5.1087 }}</ref>
* [[RHEB]],<ref name=pmid15854902/><ref name="pmid15878852">{{cite journal | vauthors = Long X, Ortiz-Vega S, Lin Y, Avruch J | title = Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency | journal = The Journal of Biological Chemistry | volume = 280 | issue = 25 | pages = 23433–6 | date = June 2005 | pmid = 15878852 | doi = 10.1074/jbc.C500169200 }}</ref><ref name="pmid15772076">{{cite journal | vauthors = Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG | title = The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses | journal = The Journal of Biological Chemistry | volume = 280 | issue = 19 | pages = 18717–27 | date = May 2005 | pmid = 15772076 | doi = 10.1074/jbc.M414499200 }}</ref><ref name="pmid16915281">{{cite journal | vauthors = Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP | title = PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR | journal = Nature | volume = 442 | issue = 7104 | pages = 779–85 | date = August 2006 | pmid = 16915281 | doi = 10.1038/nature05029 }}</ref>
* [[RICTOR]],<ref name=pmid15467718/><ref name=pmid16919458/><ref name=pmid15268862/><ref name=pmid16962653/><ref name=pmid16603397/><ref name=pmid16183647/><ref name=pmid17043309/>
* [[P70-S6 Kinase 1|RPS6KB1]],<ref name=pmid12150925/><ref name=pmid12150926/><ref name=pmid15854902/><ref name=pmid10971657/><ref name=pmid9465032/><ref name=pmid12604610/><ref name=pmid16183647/><ref name="pmid11914378">{{cite journal | vauthors = Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis PB, Thomas G | title = Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site | journal = The Journal of Biological Chemistry | volume = 277 | issue = 22 | pages = 20104–12 | date = May 2002 | pmid = 11914378 | doi = 10.1074/jbc.M201745200 }}</ref><ref name="pmid15899889">{{cite journal | vauthors = Chiang GG, Abraham RT | title = Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase | journal = The Journal of Biological Chemistry | volume = 280 | issue = 27 | pages = 25485–90 | date = July 2005 | pmid = 15899889 | doi = 10.1074/jbc.M501707200 }}</ref><ref name="pmid15905173">{{cite journal | vauthors = Holz MK, Blenis J | title = Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase | journal = The Journal of Biological Chemistry | volume = 280 | issue = 28 | pages = 26089–93 | date = July 2005 | pmid = 15905173 | doi = 10.1074/jbc.M504045200 }}</ref><ref name="pmid10567431">{{cite journal | vauthors = Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K | title = Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro | journal = The Journal of Biological Chemistry | volume = 274 | issue = 48 | pages = 34493–8 | date = November 1999 | pmid = 10567431 | doi = 10.1074/jbc.274.48.34493 }}</ref><ref name="pmid15896331">{{cite journal | vauthors = Toral-Barza L, Zhang WG, Lamison C, Larocque J, Gibbons J, Yu K | title = 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 | journal = Biochemical and Biophysical Research Communications | volume = 332 | issue = 1 | pages = 304–10 | date = June 2005 | pmid = 15896331 | doi = 10.1016/j.bbrc.2005.04.117 }}</ref><ref name="pmid15809305">{{cite journal | vauthors = Ali SM, Sabatini DM | title = Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site | journal = The Journal of Biological Chemistry | volume = 280 | issue = 20 | pages = 19445–8 | date = May 2005 | pmid = 15809305 | doi = 10.1074/jbc.C500125200 }}</ref><ref name="pmid15809305"/><ref name="pmid14679009">{{cite journal | vauthors = Edinger AL, Linardic CM, Chiang GG, Thompson CB, Abraham RT | title = Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells | journal = Cancer Research | volume = 63 | issue = 23 | pages = 8451–60 | date = December 2003 | pmid = 14679009 | doi =  }}</ref><ref name="pmid16922504">{{cite journal | vauthors = Leone M, Crowell KJ, Chen J, Jung D, Chiang GG, Sareth S, Abraham RT, Pellecchia M | title = The FRB domain of mTOR: NMR solution structure and inhibitor design | journal = Biochemistry | volume = 45 | issue = 34 | pages = 10294–302 | date = August 2006 | pmid = 16922504 | doi = 10.1021/bi060976 }}</ref>
* [[STAT1]],<ref name="pmid12807916">{{cite journal | vauthors = Kristof AS, Marks-Konczalik J, Billings E, Moss J | title = 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 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 36 | pages = 33637–44 | date = September 2003 | pmid = 12807916 | doi = 10.1074/jbc.M301053200 }}</ref>
* [[STAT3]],<ref name="pmid10660304">{{cite journal | vauthors = Yokogami K, Wakisaka S, Avruch J, Reeves SA | title = Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR | journal = Current Biology | volume = 10 | issue = 1 | pages = 47–50 | date = January 2000 | pmid = 10660304 | doi = 10.1016/S0960-9822(99)00268-7 }}</ref><ref name="pmid15522880">{{cite journal | vauthors = Kusaba H, Ghosh P, Derin R, Buchholz M, Sasaki C, Madara K, Longo DL | title = Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR) | journal = The Journal of Biological Chemistry | volume = 280 | issue = 2 | pages = 1037–43 | date = January 2005 | pmid = 15522880 | doi = 10.1074/jbc.M405204200 }}</ref>
*[[Two-pore channels]]: [[TPCN1]]; [[TPCN2]],<ref>{{cite journal | vauthors = Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K, Shi L, Battaglia-Hsu S, Nissim I, Clapham DE, Ren D | title = mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state | journal = Cell | volume = 152 | issue = 4 | pages = 778–90 | date = February 2013 | pmid = 23394946 | doi = 10.1016/j.cell.2013.01.023 | pmc=3908667}}</ref> and
* [[UBQLN1]].<ref name="pmid11853878">{{cite journal | vauthors = Wu S, Mikhailov A, Kallo-Hosein H, Hara K, Yonezawa K, Avruch J | title = Characterization of ubiquilin 1, an mTOR-interacting protein | journal = Biochimica et Biophysica Acta | volume = 1542 | issue = 1–3 | pages = 41–56 | date = January 2002 | pmid = 11853878 | doi = 10.1016/S0167-4889(01)00164-1 }}</ref>
{{Div col end}}

== References ==
{{reflist|35em}}

== Further reading ==
* {{cite journal | vauthors = Saxton RA, Sabatini DM | title = mTOR Signaling in Growth, Metabolism, and Disease | journal = Cell | volume = 168 | issue = 6 | pages = 960–976 | date = March 2017 | pmid = 28283069 | pmc = 5394987 | doi = 10.1016/j.cell.2017.02.004 }}

== External links ==
* {{MeshName|mTOR+protein}}
* {{cite web | url = http://pid.nci.nih.gov/search/pathway_landing.shtml?pathway_id=100101&pathway_name=mtor%20signaling%20pathway&source=BioCarta%20Imported&what=graphic&jpg=on&ppage=1 | publisher = National Cancer Institute | title = mTOR Signaling Pathway in Pathway Interaction Database }}

{{PDB Gallery|geneid=2475}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
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{{DEFAULTSORT:Mammalian Target Of Rapamycin}}
[[Category:EC 2.7.11]]
[[Category:Signal transduction]]
[[Category:Tor signaling pathway]]
[[Category:Human proteins]]
[[Category:Aging-related proteins]]