View source for MTORC1

{{lowercase title}}
{{infobox protein
| Name = [[Mammalian target of rapamycin|mTOR]]
| caption = 
| image = 
| width = 
| HGNCid = 3942
| Symbol = [[Mammalian target of rapamycin|MTOR]]
| AltSymbols = FRAP, FRAP2, FRAP1
| EntrezGene = 2475
| OMIM = 601231
| RefSeq = NM_004958
| UniProt = P42345
| PDB = 
| ECnumber = 2.7.11.1
| Chromosome = 1
| Arm = p
| Band = 36
| LocusSupplementaryData = 
}}
{{lowercase title}}
{{infobox protein
| Name = [[RPTOR]]
| caption = 
| image = 
| width = 
| HGNCid = 30287
| Symbol = [[RPTOR]]
| AltSymbols = KOG1, Mip1
| EntrezGene = 57521
| OMIM = 607130
| RefSeq = NM_001163034.1
| UniProt = Q8N122
| PDB = 
| ECnumber = 
| Chromosome = 17
| Arm = q
| Band = 25.3
| LocusSupplementaryData = 
}}

'''mTORC1''', also known as '''mammalian target of rapamycin complex 1''' or '''mechanistic target of rapamycin complex 1''', is a [[protein complex]] that functions as a nutrient/energy/redox sensor and controls protein synthesis.<ref name="Hay_2004">{{cite journal | vauthors = Hay N, Sonenberg N | title = Upstream and downstream of mTOR | journal = Genes & Development | volume = 18 | issue = 16 | pages = 1926–45 | date = Aug 2004 | pmid = 15314020 | doi = 10.1101/gad.1212704 }}</ref><ref name="Kim_2002">{{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 = Jul 2002 | pmid = 12150925 | doi = 10.1016/S0092-8674(02)00808-5 }}</ref>

mTOR Complex 1 (mTORC1) is composed of [[mammalian target of rapamycin|mTOR]] itself, regulatory-associated protein of mTOR ([[RPTOR|Raptor]]), mammalian lethal with SEC13 protein 8  ([[MLST8]]) and the recently identified [[AKT1S1|PRAS40]] and [[DEPTOR]].<ref name="Kim_2002"/><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 = Apr 2003 | pmid = 12718876 | doi = 10.1016/S1097-2765(03)00114-X }}</ref><ref name="pmid16469695">{{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 = Feb 2006 | pmid = 16469695 | doi = 10.1016/j.cell.2006.01.016 }}</ref> This complex embodies the classic functions of mTOR, namely as a nutrient/energy/redox sensor and controller of protein synthesis.<ref name="Hay_2004"/><ref name=Kim_2002/> The activity of this complex 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=Kim_2002/><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 = Nov 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>

The role of mTORC1 is to activate translation of proteins. In order for cells to grow and proliferate by manufacturing more proteins, the cells must ensure that they have the resources available for protein production. Thus, for protein production, and therefore mTORC1 activation, cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation to begin.<ref name="pmid16469695"/>

== Activation at the lysosome ==

[[File:Activation of mTORC1 at the Lysosome.jpg|thumb|left|150px|Activation of mTORC1 at the [[lysosome]].]]

=== The TSC complex ===

Almost all of the variables required for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 protein complex. [[TSC2]] is a [[GTPase]] activating protein ([[GTPase-activating protein|GAP]]). Its GAP activity interacts with a G protein called [[Rheb]] by hydrolyzing the [[guanosine triphosphate|GTP]] of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The active Rheb-GTP activates mTORC1 through unelucidated pathways.<ref name="pmid23246968">{{cite journal | vauthors = Beauchamp EM, Platanias LC | title = The evolution of the TOR pathway and its role in cancer | journal = Oncogene | volume = 32 | issue = 34 | pages = 3923–32 | date = Aug 2013 | pmid = 23246968 | doi = 10.1038/onc.2012.567 }}</ref>  Thus, many of the pathways that influence mTORC1 activation do so through the activation or inactivation of the TSC1/TSC2 [[heterodimer]]. This control is usually performed through [[phosphorylation]] of the complex. This phosphorylation can cause the dimer to dissociate and lose its GAP activity, or the phosphorylation can cause the heterodimer to have increased GAP activity, depending on which amino acid residue becomes phosphorylated.<ref name="pmid22240970">{{cite journal | vauthors = Durán RV, Hall MN | title = Regulation of TOR by small GTPases | journal = EMBO Reports | volume = 13 | issue = 2 | pages = 121–8 | date = Feb 2012 | pmid = 22240970 | pmc = 3271343 | doi = 10.1038/embor.2011.257 }}</ref> Thus, the signals that influence mTORC1 activity do so through activation or inactivation of the TSC1/TSC2 complex, upstream of mTORC1.

=== The Rag complex ===

mTORC1 signaling is sensitive to amino acid levels in the cell.<ref name="pmid23361334">{{cite journal | vauthors = Jewell JL, Russell RC, Guan KL | title = Amino acid signalling upstream of mTOR | journal = Nature Reviews Molecular Cell Biology | volume = 14 | issue = 3 | pages = 133–9 | date = Mar 2013 | pmid = 23361334 | doi = 10.1038/nrm3522 | pmc=3988467}}</ref> Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Studies have shown that depriving amino acid levels inhibits mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes '''Rag GTPase'''<!--bolded per MOS:BOLD - term redirects here--> heterodimers to switch to their active conformation.<ref name="pmid22749019">{{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 = Sep 2012 | pmid = 22749019 | doi = 10.1016/j.molmed.2012.05.007 | pmc=3432651}}</ref> Active Rag heterodimers interact with Raptor, localizing mTORC1 to the surface of late [[endosome]]s and [[lysosome]]s where the Rheb-GTP is located.<ref name="pmid18497260">{{cite journal | vauthors = Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM | title = The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1 | journal = Science | volume = 320 | issue = 5882 | pages = 1496–501 | date = Jun 2008 | pmid = 18497260 | pmc = 2475333 | doi = 10.1126/science.1157535 }}</ref>  This allows mTORC1 to physically interact with Rheb. Thus the amino acid pathway as well as the growth factor/energy pathway converge on endosomes and lysosomes. Thus the Rag complex recruits mTORC1 to lysosomes to interact with Rheb.<ref name="pmid12766776">{{cite journal | vauthors = Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA | title = Rheb promotes cell growth as a component of the insulin/TOR signalling network | journal = Nature Cell Biology | volume = 5 | issue = 6 | pages = 566–71 | date = Jun 2003 | pmid = 12766776 | doi = 10.1038/ncb996 }}</ref><ref name="pmid21785113">{{cite journal | vauthors = Suzuki T, Inoki K | title = Spatial regulation of the mTORC1 system in amino acids sensing pathway | journal = Acta Biochimica et Biophysica Sinica | volume = 43 | issue = 9 | pages = 671–9 | date = Sep 2011 | pmid = 21785113 | pmc = 3160786 | doi = 10.1093/abbs/gmr066 }}</ref>

==== Regulation of the Rag complex ====

Rag activity is regulated by at least two highly conserved complexes: the "GATOR1" complex containing [[DEPDC5]], [[NPRL2]] and [[NPRL3]] and the ""GATOR2" complex containing [[Mios]], [[WDR24]], [[WDR59]], [[Seh1L]], [[Sec13]].<ref>{{cite journal | vauthors = Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM | title = A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1 | journal = Science | volume = 340 | issue = 6136 | pages = 1100–6  | date = May 2013 | pmid = 23723238 | pmc = 3728654 | doi = 10.1126/science.1232044 }}</ref> GATOR1 inhibits Rags (it is a [[GTPase-activating protein]] for Rag subunits A/B) and GATOR2 activates Rags by inhibiting [[DEPDC5]].

== Upstream signaling ==

[[File:General mTORC1 Pathway.jpg|thumb|left|150px|The General mTORC1 Pathway.]]

=== Receptor tyrosine kinases ===

==== Akt/PKB pathway ====

Insulin-like growth factors can activate mTORC1 through the [[receptor tyrosine kinase]] (RTK)-[[Akt/PKB signaling pathway]]. Ultimately, [[Akt]] phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462.<ref name="pmid19339977">{{cite journal | vauthors = Ma XM, Blenis J | title = Molecular mechanisms of mTOR-mediated translational control | journal = Nature Reviews Molecular Cell Biology | volume = 10 | issue = 5 | pages = 307–18 | date = May 2009 | pmid = 19339977 | doi = 10.1038/nrm2672 }}</ref> These phosphorylated sites will recruit the cytosolic anchoring protein [[14-3-3]] to TSC2, disrupting the TSC1/TSC2 dimer. When TSC2 is not associated with TSC1, TSC2 loses its GAP activity and can no longer hydrolyze Rheb-GTP. This results in continued activation of mTORC1, allowing for protein synthesis via insulin signaling.<ref name="pmid21531565">{{cite journal | vauthors = Mendoza MC, Er EE, Blenis J | title = The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation | journal = Trends in Biochemical Sciences | volume = 36 | issue = 6 | pages = 320–8 | date = Jun 2011 | pmid = 21531565 | pmc = 3112285 | doi = 10.1016/j.tibs.2011.03.006 }}</ref>

Akt will also phosphorylate PRAS40, causing it to fall off of the Raptor protein located on mTORC1. Since PRAS40 prevents Raptor from recruiting mTORC1's substrates [[4E-BP1]] and [[S6K1]], its removal will allow the two substrates to be recruited to mTORC1 and thereby activated in this way.<ref name="pmid17517883">{{cite journal | vauthors = Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, Kikkawa U, Yonezawa K | title = The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 28 | pages = 20329–39 | date = Jul 2007 | pmid = 17517883 | pmc = 3199301 | doi = 10.1074/jbc.M702636200 }}</ref>

Furthermore, since insulin is a factor that is secreted by pancreatic [[beta cells]] upon [[glucose]] elevation in the blood, its signaling ensures that there is energy for protein synthesis to take place. In a [[negative feedback loop]] on mTORC1 signaling, S6K1 is able to phosphorylate the [[insulin receptor]] and inhibit its sensitivity to insulin.<ref name="pmid19339977" /> This has great significance in [[diabetes mellitus]], which is due to [[insulin resistance]].<ref name="pmid23471659">{{cite journal | vauthors = Ye J | title = Mechanisms of insulin resistance in obesity | journal = Frontiers of Medicine | volume = 7 | issue = 1 | pages = 14–24 | date = Mar 2013 | pmid = 23471659 | doi = 10.1007/s11684-013-0262-6 | pmc=3936017}}</ref>

==== MAPK/ERK pathway ====

Mitogens, such as insulin like growth factor 1 ([[IGF1]]), can activate the [[MAPK/ERK pathway]], which can inhibit the TSC1/TSC2 complex, activating mTORC1.<ref name="pmid21531565"/> In this pathway, the G protein Ras is tethered to the plasma membrane via a [[farnesyl]] group and is in its inactive GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein [[GRB2]] binds with its [[SH2 domain]]s. This recruits the GEF called Sos, which activates the Ras G protein. Ras activates [[Raf kinase|Raf]] (MAPKKK), which activates [[mitogen-activated protein kinase kinase|Mek]] (MAPKK), which activates [[extracellular signal-regulated kinases|Erk]] (MAPK).<ref name="pmid23085539">{{cite journal | vauthors = McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Franklin RA, Montalto G, Cervello M, Libra M, Candido S, Malaponte G, Mazzarino MC, Fagone P, Nicoletti F, Bäsecke J, Mijatovic S, Maksimovic-Ivanic D, Milella M, Tafuri A, Chiarini F, Evangelisti C, Cocco L, Martelli AM | title = Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance | journal = Oncotarget | volume = 3 | issue = 10 | pages = 1068–111 | date = Oct 2012 | pmid = 23085539 | doi =  10.18632/oncotarget.659 | pmc=3717945}}</ref> Erk can go on to activate [[ribosomal s6 kinase|RSK]]. Erk will phosphorylate the serine residue 644 on TSC2, while RSK will phosphorylate serine residue 1798 on TSC2.<ref name="pmid15851026">{{cite journal | vauthors = Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP | title = Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis | journal = Cell | volume = 121 | issue = 2 | pages = 179–93 | date = Apr 2005 | pmid = 15851026 | doi = 10.1016/j.cell.2005.02.031 }}</ref> These phosphorylations will cause the heterodimer to fall apart, and prevent it from deactivating Rheb, which keeps mTORC1 active.

RSK has also been shown to phosphorylate [[RPTOR|raptor]], which helps it overcome the inhibitory effects of [[AKT1S1|PRAS40]].<ref name="pmid18722121">{{cite journal | vauthors = Carrière A, Cargnello M, Julien LA, Gao H, Bonneil E, Thibault P, Roux PP | title = Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation | journal = Current Biology | volume = 18 | issue = 17 | pages = 1269–77 | date = Sep 2008 | pmid = 18722121 | doi = 10.1016/j.cub.2008.07.078 }}</ref>

=== Wnt pathway ===

The [[Wnt pathway]] is responsible for cellular growth and proliferation during organismal development; thus, it could be reasoned that activation of this pathway also activates mTORC1. Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta ([[GSK3B]]).<ref name="pmid22325146">{{cite journal | vauthors = Majid S, Saini S, Dahiya R | title = Wnt signaling pathways in urological cancers: past decades and still growing | journal = Molecular Cancer | volume = 11 | issue =  | pages = 7 | year = 2012 | pmid = 22325146 | pmc = 3293036 | doi = 10.1186/1476-4598-11-7 }}</ref> When the Wnt pathway is not active, GSK3 beta is able to phosphorylate TSC2 on two serine residues of 1341 and 1337 in conjunction with AMPK phosphorylating serine residue 1345. It has been found that the AMPK is required to first phosphorylate residue 1345 before GSK3 beta can phosphorylate its target serine residues. This phosphorylation of TSC2 would inactivate this complex, if GSK3 beta were active. Since the Wnt pathway inhibits GSK3 signaling, the active Wnt pathway is also involved in the mTORC1 pathway. Thus, mTORC1 can activate protein synthesis for the developing organism.<ref name="pmid22325146"/>

=== Cytokines ===

[[Cytokines]] like [[tumor necrosis factor alpha]] (TNF-alpha) can induce mTOR activity through IKK beta, also known as [[IKK2]].<ref name="pmid22899934">{{cite journal | vauthors = Salminen A, Hyttinen JM, Kauppinen A, Kaarniranta K | title = Context-Dependent Regulation of Autophagy by IKK-NF-κB Signaling: Impact on the Aging Process | journal = International Journal of Cell Biology | volume = 2012 | issue =  | pages = 849541 | year = 2012 | pmid = 22899934 | pmc = 3412117 | doi = 10.1155/2012/849541 }}</ref> IKK beta can phosphorylate TSC1 at serine residue 487 and TSC1 at serine residue 511. This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP-bound state.

=== Energy and oxygen ===

==== Energy status ====

In order for translation to take place, abundant sources of energy, particularly in the form of [[adenosine triphosphate|ATP]], need to be present. If these levels of ATP are not present, due to its hydrolysis into other forms like [[adenosine monophosphate|AMP]], and the ratio of AMP to ATP molecules gets too high, [[AMP-activated protein kinase|AMPK]] will become activated. AMPK will go on to inhibit energy consuming pathways such as protein synthesis.<ref name="pmid17712357">{{cite journal | vauthors = Hardie DG | title = AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy | journal = Nature Reviews Molecular Cell Biology | volume = 8 | issue = 10 | pages = 774–85 | date = Oct 2007 | pmid = 17712357 | doi = 10.1038/nrm2249 }}</ref>

AMPK can phosphorylate TSC2 on serine residue 1387, which activates the GAP activity of this complex, causing Rheb-GTP to be hydrolyzed into Rheb-GDP. This inactivates mTORC1 and blocks protein synthesis through this pathway.<ref name="pmid21892142">{{cite journal | vauthors = Mihaylova MM, Shaw RJ | title = The AMPK signalling pathway coordinates cell growth, autophagy and metabolism | journal = Nature Cell Biology | volume = 13 | issue = 9 | pages = 1016–23 | date = Sep 2011 | pmid = 21892142 | pmc = 3249400 | doi = 10.1038/ncb2329 }}</ref>

AMPK can also phosphorylate Raptor on two serine residues. This phosphorylated Raptor recruits 14-3-3 to bind to it and prevents Raptor from being part of the mTORC1 complex. Since mTORC1 cannot recruit its substrates without Raptor, no protein synthesis via mTORC1 occurs.<ref name="pmid18439900">{{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 = Apr 2008 | pmid = 18439900 | pmc = 2674027 | doi = 10.1016/j.molcel.2008.03.003 }}</ref>

LKB1, also known as [[STK11]], is a known [[tumor suppressor]] that can activate AMPK. More studies on this aspect of mTORC1 may help shed light on its strong link to cancer.<ref name="pmid22353783">{{cite journal | vauthors = Nagalingam A, Arbiser JL, Bonner MY, Saxena NK, Sharma D | title = Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis | journal = Breast Cancer Research : BCR | volume = 14 | issue = 1 | pages = R35 | year = 2012 | pmid = 22353783 | pmc = 3496153 | doi = 10.1186/bcr3128 }}</ref>

==== Hypoxic stress ====

When oxygen levels in the cell are low, it will limit its energy expenditure through the inhibition of protein synthesis. Under [[hypoxia (medical)|hypoxic]] conditions, hypoxia inducible factor one alpha ([[HIF1A]]) will stabilize and activate transcription of REDD1, also known as [[DDIT4]]. After translation, this REDD1 protein will bind to TSC2, which prevents 14-3-3 from inhibiting the TSC complex. Thus, TSC retains its GAP activity towards Rheb, causing Rheb to remain bound to GDP and mTORC1 to be inactive.<ref name="pmid20176937">{{cite journal | vauthors = Horak P, Crawford AR, Vadysirisack DD, Nash ZM, DeYoung MP, Sgroi D, Ellisen LW | title = Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 10 | pages = 4675–80 | date = Mar 2010 | pmid = 20176937 | pmc = 2842042 | doi = 10.1073/pnas.0907705107 }}</ref><ref name="pmid15545625">{{cite journal | vauthors = Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG | title = Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex | journal = Genes & Development | volume = 18 | issue = 23 | pages = 2893–904 | date = Dec 2004 | pmid = 15545625 | pmc = 534650 | doi = 10.1101/gad.1256804 }}</ref>

Due to the lack of synthesis of ATP in the mitochondria under hypoxic stress or hypoxia, AMPK will also become active and thus inhibit mTORC1 through its processes.<ref name="pmid22390198">{{cite journal | vauthors = Wang S, Song P, Zou MH | title = AMP-activated protein kinase, stress responses and cardiovascular diseases | journal = Clinical Science | volume = 122 | issue = 12 | pages = 555–73 | date = Jun 2012 | pmid = 22390198 | pmc = 3367961 | doi = 10.1042/CS20110625 }}</ref>

== Downstream signaling ==

[[File:Downstream of mTORC1.png|thumb|left|150px|Receptor Tyrosine Kinases and mTORC1.]]

mTORC1 activates transcription and translation through its interactions with [[p70-S6 Kinase 1]] (S6K1) and [[4E-BP1]], the [[eIF4E|eukaryotic initiation factor 4E]] (eIF4E) binding protein 1.<ref name="Hay_2004"/> Their signaling will converge at the translation initiation complex on the 5' end of mRNA, and thus activate translation.

=== 4E-BP1 ===

Activated mTORC1 will phosphorylate [[translation inhibitor]] [[4E-BP1]], releasing it from eukaryotic translation initiation factor 4E ([[eIF4E]]).<ref name="pmid21436840">{{cite journal | vauthors = Martelli AM, Evangelisti C, Chappell W, Abrams SL, Bäsecke J, Stivala F, Donia M, Fagone P, Nicoletti F, Libra M, Ruvolo V, Ruvolo P, Kempf CR, Steelman LS, McCubrey JA | title = Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway | journal = Leukemia | volume = 25 | issue = 7 | pages = 1064–79 | date = Jul 2011 | pmid = 21436840 | doi = 10.1038/leu.2011.46 }}</ref> eIF4E is now free to join the eukaryotic translation initiation factor 4G ([[eIF4G]]) and the eukaryotic translation initiation factor 4A ([[eIF4A]]).<ref name="pmid21906675">{{cite journal | vauthors = Wang H, Zhang Q, Wen Q, Zheng Y, Lazarovici P, Philip L, Jiang H, Lin J, Zheng W | title = Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway | journal = Cellular Signalling | volume = 24 | issue = 1 | pages = 17–24 | date = Jan 2012 | pmid = 21906675 | doi = 10.1016/j.cellsig.2011.08.010 }}</ref> This complex then binds to the 5' cap of mRNA and will recruit the [[helicase]] eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B ([[eIF4B]]).<ref name="pmid10216943">{{cite journal | vauthors = Raught B, Gingras AC | title = eIF4E activity is regulated at multiple levels | journal = The International Journal of Biochemistry & Cell Biology | volume = 31 | issue = 1 | pages = 43–57 | date = Jan 1999 | pmid = 10216943 | doi = 10.1016/s1357-2725(98)00131-9 }}</ref> The helicase is required to remove hairpin loops that arise in the [[5' untranslated regions]] of [[mRNA]], which prevent premature translation of proteins. Once the initiation complex is assembled at the 5' cap of mRNA, it will recruit the [[40S]] small ribosomal subunit that is now capable of scanning for the AUG [[start codon]] start site, because the [[hairpin loop]] has been eradicated by the eIF4A helicase.<ref name="pmid22168162">{{cite journal | vauthors = Lee T, Pelletier J | title = Eukaryotic initiation factor 4F: a vulnerability of tumor cells | journal = Future Medicinal Chemistry | volume = 4 | issue = 1 | pages = 19–31 | date = Jan 2012 | pmid = 22168162 | doi = 10.4155/fmc.11.150 }}</ref> Once the ribosome reaches the AUG codon, translation can begin.

=== S6K ===

Hypophosphorylated S6K is located on the [[eukaryotic initiation factor#eIF1 & eIF3|eIF3]] scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.<ref name="pmid19339977"/>

mTORC1 [[phosphorylate]]s S6K1 on at least two residues, with the most critical modification occurring on a [[threonine]] residue (T389)<!--Thr389-->.<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=Pullen1997>{{cite journal | vauthors = Pullen N, Thomas G | title = The modular phosphorylation and activation of p70s6k | journal = FEBS Letters | volume = 410 | issue = 1 | pages = 78–82 | date = Jun 1997 | pmid = 9247127 | doi = 10.1016/S0014-5793(97)00323-2 }}</ref> This event stimulates the subsequent phosphorylation of S6K1 by [[PDPK1|PDK1]].<ref name=Pullen1997/><ref name=Pullen1998>{{cite journal | vauthors = Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G | title = Phosphorylation and activation of p70s6k by PDK1 | journal = Science | volume = 279 | issue = 5351 | pages = 707–10 | date = Jan 1998 | pmid = 9445476 | doi = 10.1126/science.279.5351.707 }}</ref>  Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the [[ribosome]]) and eIF4B, causing them to be recruited to the pre-initiation complex.<ref name=Peterson>{{cite journal | vauthors = Peterson RT, Schreiber SL | title = Translation control: connecting mitogens and the ribosome | journal = Current Biology | volume = 8 | issue = 7 | pages = R248–50 | date = Mar 1998 | pmid = 9545190 | doi = 10.1016/S0960-9822(98)70152-6 }}</ref>

Active S6K can bind to the SKAR [[scaffold protein]] that can get recruited to exon junction complexes ([[exon junction complex|EJC]]). Exon junction complexes span the mRNA region where two [[exons]] come together after an [[intron]] has been spliced out. Once S6K binds to this complex, increased translation on these mRNA regions occurs.<ref name="pmid18423201">{{cite journal | vauthors = Ma XM, Yoon SO, Richardson CJ, Jülich K, Blenis J | title = SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs | journal = Cell | volume = 133 | issue = 2 | pages = 303–13 | date = Apr 2008 | pmid = 18423201 | doi = 10.1016/j.cell.2008.02.031 }}</ref>

S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites<!--threonine2446 and serine2448-->; phosphorylation at these sites appears to stimulate mTOR activity.<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 = Jul 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 = Jul 2005 | pmid = 15905173 | doi = 10.1074/jbc.M504045200 }}</ref>

S6K also can phosphorylate programmed cell death 4 ([[PDCD4]]), which marks it for degradation by [[ubiquitin ligase]] Beta-TrCP ([[BTRC (gene)|BTRC]]). PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex.<ref name="pmid18296647">{{cite journal | vauthors = Schmid T, Jansen AP, Baker AR, Hegamyer G, Hagan JP, Colburn NH | title = Translation inhibitor Pdcd4 is targeted for degradation during tumor promotion | journal = Cancer Research | volume = 68 | issue = 5 | pages = 1254–60 | date = Mar 2008 | pmid = 18296647 | doi = 10.1158/0008-5472.CAN-07-1719 }}</ref>

== Role in disease and aging ==

mTOR was found to be related to aging in 2001 when the ortholog of S6K, SCH9, was deleted in ''S. cerevisiae'', doubling its lifespan.<ref name="pmid11292860">{{cite journal | vauthors = Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD | title = Regulation of longevity and stress resistance by Sch9 in yeast | journal = Science | volume = 292 | issue = 5515 | pages = 288–90 | date = Apr 2001 | pmid = 11292860 | doi = 10.1126/science.1059497 }}</ref> This greatly increased the interest in upstream signaling and mTORC1. Studies in inhibiting mTORC1 were thus performed on the model organisms of  ''C. elegans'', fruitflies, and mice. Inhibition of mTORC1 showed significantly increased lifespans in all model species.<ref name="pmid22560223">{{cite journal | vauthors = Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E, Sabatini DM, Blackwell TK | title = TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO | journal = Cell Metabolism | volume = 15 | issue = 5 | pages = 713–24 | date = May 2012 | pmid = 22560223 | doi = 10.1016/j.cmet.2012.04.007 | pmc=3348514}}</ref><ref name="pmid19587680">{{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 = Jul 2009 | pmid = 19587680 | pmc = 2786175 | doi = 10.1038/nature08221 }}</ref>

Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed.<ref name="pmid16293764">{{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 = Nov 2005 | pmid = 16293764 | doi = 10.1126/science.1115535 }}</ref> Most specifically, carbohydrate consumption activates mTORC1 through the [[insulin growth factor]] pathway. In addition, amino acid consumption will stimulate mTORC1 through the branched chain amino acid/Rag pathway. Thus dietary restriction inhibits mTORC1 signaling through both upstream pathways of mTORC that converge on the [[lysosome]].<ref name="pmid20139716">{{cite journal | vauthors = Blagosklonny MV | title = Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans) | journal = Cell Cycle (Georgetown, Tex.) | volume = 9 | issue = 4 | pages = 683–8 | date = Feb 2010 | pmid = 20139716 | doi = 10.4161/cc.9.4.10766 }}</ref>

Dietary restriction has been shown to significantly increase lifespan in the human model of [[Rhesus monkeys]] as well as protect against their age related decline.<ref name="pmid19590001">{{cite journal | vauthors = Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R | title = Caloric restriction delays disease onset and mortality in rhesus monkeys | journal = Science | volume = 325 | issue = 5937 | pages = 201–4 | date = Jul 2009 | pmid = 19590001 | pmc = 2812811 | doi = 10.1126/science.1173635 }}</ref> More specifically, Rhesus monkeys on a calorie restricted diet had significantly less chance of developing [[cardiovascular disease]], [[diabetes]], [[cancer]], and age related cognitive decline than those monkeys who were not placed on the calorie restricted diet.<ref name="pmid19590001" />

=== Autophagy ===

[[Autophagy]] is the major degradation pathway in [[eukaryotic cells]] and is essential for the removal of damaged [[organelles]] via [[macroautophagy]] or proteins and smaller cellular debris via microautophagy from the [[cytoplasm]].<ref name="pmid23406030">{{cite journal | vauthors = Choi AM, Ryter SW, Levine B | title = Autophagy in human health and disease | journal = The New England Journal of Medicine | volume = 368 | issue = 7 | pages = 651–62 | date = Feb 2013 | pmid = 23406030 | doi = 10.1056/NEJMra1205406 }}</ref> Thus, autophagy is a way for the cell to recycle old and damaged materials by breaking them down into their smaller components, allowing for the resynthesis of newer and healthier cellular structures.<ref name="pmid23406030" /> Autophagy can thus remove [[protein aggregates]] and damaged organelles, that can lead to cellular dysfunction.<ref name="pmid23072311">{{cite journal | vauthors = Murrow L, Debnath J | title = Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease | journal = Annual Review of Pathology | volume = 8 | issue =  | pages = 105–37 | date = Jan 2013 | pmid = 23072311 | doi = 10.1146/annurev-pathol-020712-163918 | pmc=3971121}}</ref>

Upon activation, mTORC1 will phosphorylate [[autophagy-related protein 13]] (Atg 13), preventing it from entering the [[ULK1]] kinase complex, which consists of [[Atg1]], Atg17, and Atg101.<ref name="pmid22025673">{{cite journal | vauthors = Alers S, Löffler AS, Wesselborg S, Stork B | title = Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks | journal = Molecular and Cellular Biology | volume = 32 | issue = 1 | pages = 2–11 | date = Jan 2012 | pmid = 22025673 | pmc = 3255710 | doi = 10.1128/MCB.06159-11 }}</ref> This prevents the structure from being recruited to the preautophagosomal structure at the [[plasma membrane]], inhibiting autophagy.<ref name="pmid22257882">{{cite journal | vauthors = Pyo JO, Nah J, Jung YK | title = Molecules and their functions in autophagy | journal = Experimental & Molecular Medicine | volume = 44 | issue = 2 | pages = 73–80 | date = Feb 2012 | pmid = 22257882 | pmc = 3296815 | doi = 10.3858/emm.2012.44.2.029 }}</ref>

mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level.<ref name="pmid17956308">{{cite journal | vauthors = Proud CG | title = Amino acids and mTOR signalling in anabolic function | journal = Biochemical Society Transactions | volume = 35 | issue = Pt 5 | pages = 1187–90 | date = Nov 2007 | pmid = 17956308 | doi = 10.1042/BST0351187 }}</ref> Because autophagy appears to decline with age, activation of autophagy may help promote longevity in humans.<ref name="pmid10806201">{{cite journal | vauthors = Cuervo AM, Dice JF | title = Age-related decline in chaperone-mediated autophagy | journal = The Journal of Biological Chemistry | volume = 275 | issue = 40 | pages = 31505–13 | date = Oct 2000 | pmid = 10806201 | doi = 10.1074/jbc.M002102200 }}</ref> Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.<ref name="pmid16247498">{{cite journal | vauthors = Codogno P, Meijer AJ | title = Autophagy and signaling: their role in cell survival and cell death | journal = Cell Death and Differentiation | volume = 12 Suppl 2 | issue =  | pages = 1509–18 | date = Nov 2005 | pmid = 16247498 | doi = 10.1038/sj.cdd.4401751 }}</ref>

=== Reactive oxygen species ===

[[Reactive oxygen species]] can damage the DNA and proteins in cells.<ref name="pmid15377225">{{cite journal | vauthors = Apel K, Hirt H | title = Reactive oxygen species: metabolism, oxidative stress, and signal transduction | journal = Annual Review of Plant Biology | volume = 55 | issue =  | pages = 373–99 | year = 2004 | pmid = 15377225 | doi = 10.1146/annurev.arplant.55.031903.141701 }}</ref> A majority of them arise in the [[mitochondria]].<ref name="pmid19061483">{{cite journal | vauthors = Murphy MP | title = How mitochondria produce reactive oxygen species | journal = The Biochemical Journal | volume = 417 | issue = 1 | pages = 1–13 | date = Jan 2009 | pmid = 19061483 | pmc = 2605959 | doi = 10.1042/BJ20081386 }}</ref>

Deletion of the TOR1 gene in yeast increases [[cellular respiration]] in the mitochondria by enhancing the translation of [[mitochondrial DNA]] that encodes for the complexes involved in the [[electron transport chain]].<ref name="pmid17403371">{{cite journal | vauthors = Bonawitz ND, Chatenay-Lapointe M, Pan Y, Shadel GS | title = Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression | journal = Cell Metabolism | volume = 5 | issue = 4 | pages = 265–77 | date = Apr 2007 | pmid = 17403371 | pmc = 3460550 | doi = 10.1016/j.cmet.2007.02.009 }}</ref> When this electron transport chain is not as efficient, the unreduced oxygen molecules in the mitochondrial cortex may accumulate and begin to produce reactive oxygen species.<ref name="pmid16115017">{{cite journal | vauthors = Adam-Vizi V | title = Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources | journal = Antioxidants & Redox Signaling | volume = 7 | issue = 9–10 | pages = 1140–9 | year = 2005 | pmid = 16115017 | doi = 10.1089/ars.2005.7.1140 }}</ref> It is important to note that both cancer cells as well as those cells with greater levels of mTORC1 both rely more on [[glycolysis]] in the cytosol for ATP production rather than through [[oxidative phosphorylation]] in the inner membrane of the mitochondria.<ref name="pmid21325052">{{cite journal | vauthors = Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen R, Chang L, Zhang Y, Goto J, Onda H, Chen T, Wang MR, Lu Y, You H, Kwiatkowski D, Zhang H | title = Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 10 | pages = 4129–34 | date = Mar 2011 | pmid = 21325052 | pmc = 3054028 | doi = 10.1073/pnas.1014769108 }}</ref>

Inhibition of mTORC1 has also been shown to increase transcription of the [[NFE2L2]] (''NRF2'') gene, which is a transcription factor that is able to regulate the expression of [[electrophilic]] response elements as well as antioxidants in response to increased levels of reactive oxygen species.<ref name="pmid22810811">{{cite journal | vauthors = Sporn MB, Liby KT | title = NRF2 and cancer: the good, the bad and the importance of context | journal = Nature Reviews. Cancer | volume = 12 | issue = 8 | pages = 564–71 | date = Aug 2012 | pmid = 22810811 | doi = 10.1038/nrc3278 | pmc=3836441}}</ref>

Though AMPK induced eNOS has been shown to regulate mTORC1 in endothelium. Unlike the other cell type in endothelium eNOS induced mTORC1 and this pathway is required for mitochondrial biogenesis.<ref name="PMID26989010">{{cite journal | vauthors = Li C, Reif MM, Craige S, Kant S, Keaney JF  | title = Endothelial AMPK Activation Induces Mitochondrial Biogenesis and Stress Adaptation via eNOS-Dependent mTORC1 Signalingt | journal = Nitric Oxide | date = Mar 2016 | pmid = 26989010 | doi = 10.1016/j.niox.2016.03.003 | volume=55–56 | pages=45–53}}</ref>

=== Stem cells ===

Conservation of [[stem cells]] in the body has been shown to help prevent against premature [[aging]].<ref name="pmid15995659">{{cite journal | vauthors = Ho AD, Wagner W, Mahlknecht U | title = Stem cells and ageing. The potential of stem cells to overcome age-related deteriorations of the body in regenerative medicine | journal = EMBO Reports | volume = 6 Spec No | issue =  | pages = S35–8 | date = Jul 2005 | pmid = 15995659 | pmc = 1369281 | doi = 10.1038/sj.embor.7400436 }}</ref> mTORC1 activity plays a critical role in the growth and proliferation of stem cells.<ref name="pmid15254238">{{cite journal | vauthors = Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, Kiyama H, Yonezawa K, Yamanaka S | title = mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells | journal = Molecular and Cellular Biology | volume = 24 | issue = 15 | pages = 6710–8 | date = Aug 2004 | pmid = 15254238 | pmc = 444840 | doi = 10.1128/MCB.24.15.6710-6718.2004 }}</ref> Knocking out mTORC1 results in [[embryonic]] [[lethality]] due to lack of [[trophoblast]] development.<ref name="pmid15485918">{{cite journal | vauthors = Gangloff YG, Mueller M, Dann SG, Svoboda P, Sticker M, Spetz JF, Um SH, Brown EJ, Cereghini S, Thomas G, Kozma SC | title = Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development | journal = Molecular and Cellular Biology | volume = 24 | issue = 21 | pages = 9508–16 | date = Nov 2004 | pmid = 15485918 | pmc = 522282 | doi = 10.1128/MCB.24.21.9508-9516.2004 }}</ref> Treating stem cells with rapamycin will also slow their proliferation, conserving the stem cells in their undifferentiated condition.<ref name="pmid15254238" />

mTORC1 plays a role in the differentiation and proliferation of [[hematopoietic stem cells]]. Its upregulation has been shown to cause premature aging in hematopoietic stem cells. Conversely, inhibiting mTOR restores and regenerates the hematopoietic stem cell line.<ref name="pmid19934433">{{cite journal | vauthors = Chen C, Liu Y, Liu Y, Zheng P | title = mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells | journal = Science Signaling | volume = 2 | issue = 98 | pages = ra75 | year = 2009 | pmid = 19934433 | doi = 10.1126/scisignal.2000559 | pmc=4020596}}</ref> The mechanisms of mTORC1's inhibition on proliferation and differentiation of hematopoietic stem cells has yet to be fully elucidated.<ref name="pmid21791526">{{cite journal | vauthors = Russell RC, Fang C, Guan KL | title = An emerging role for TOR signaling in mammalian tissue and stem cell physiology | journal = Development | volume = 138 | issue = 16 | pages = 3343–56 | date = Aug 2011 | pmid = 21791526 | pmc = 3143559 | doi = 10.1242/dev.058230 }}</ref>

Rapamycin is used clinically as an immunosuppressant and prevents the proliferation of T cells and B cells.<ref name="pmid22888331">{{cite journal | vauthors = Limon JJ, Fruman DA | title = Akt and mTOR in B Cell Activation and Differentiation | journal = Frontiers in Immunology | volume = 3 | issue =  | pages = 228 | year = 2012 | pmid = 22888331 | pmc = 3412259 | doi = 10.3389/fimmu.2012.00228 }}</ref> Paradoxically, even though rapamycin is a federally approved [[immunosuppressant]], its inhibition of mTORC1 results in better quantity and quality of functional [[memory T cells]]. mTORC1 inhibition with rapamycin improves the ability of naïve T cells to become precursor [[memory T cells]] during the expansion phase of T cell development .<ref name="pmid19543266">{{cite journal | vauthors = Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R | title = mTOR regulates memory CD8 T-cell differentiation | journal = Nature | volume = 460 | issue = 7251 | pages = 108–12 | date = Jul 2009 | pmid = 19543266 | pmc = 2710807 | doi = 10.1038/nature08155 }}</ref> This inhibition also allows for an increase in quality of these [[memory T cells]] that become mature T cells during the contraction phase of their development.<ref name="pmid20536567">{{cite journal | vauthors = Araki K, Youngblood B, Ahmed R | title = The role of mTOR in memory CD8 T-cell differentiation | journal = Immunological Reviews | volume = 235 | issue = 1 | pages = 234–43 | date = May 2010 | pmid = 20536567 | doi = 10.1111/j.0105-2896.2010.00898.x | pmc=3760155}}</ref> mTORC1 inhibition with rapamycin has also been linked to a dramatic increase of [[B cells]] in old mice, enhancing their [[immune systems]].<ref name="pmid19934433" />  This [[paradox]] of rapamycin inhibiting the immune system response has been linked to several reasons, including its interaction with [[regulatory T cells]].<ref name="pmid20536567" />

== As a drug target ==

There have been several dietary compounds that have been suggested to inhibit mTORC1 signaling including [[EGCG]], [[resveratrol]], [[curcumin]], [[caffeine]], and [[alcohol]].<ref name="pmid20851890">{{cite journal | vauthors = Liu M, Wilk SA, Wang A, Zhou L, Wang RH, Ogawa W, Deng C, Dong LQ, Liu F | title = Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR | journal = The Journal of Biological Chemistry | volume = 285 | issue = 47 | pages = 36387–94 | date = Nov 2010 | pmid = 20851890 | pmc = 2978567 | doi = 10.1074/jbc.M110.169284 }}</ref><ref name="pmid22993301">{{cite journal | vauthors = Miwa S, Sugimoto N, Yamamoto N, Shirai T, Nishida H, Hayashi K, Kimura H, Takeuchi A, Igarashi K, Yachie A, Tsuchiya H | title = Caffeine induces apoptosis of osteosarcoma cells by inhibiting AKT/mTOR/S6K, NF-κB and MAPK pathways | journal = Anticancer Research | volume = 32 | issue = 9 | pages = 3643–9 | date = Sep 2012 | pmid = 22993301 | doi =  }}</ref>

=== First generation inhibitors ===
[[Rapamycin]] was the first known inhibitor of mTORC1, considering that mTORC1 was discovered as being the target of rapamycin.<ref name="pmid1102508">{{cite journal | vauthors = Vézina C, Kudelski A, Sehgal SN | title = Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle | journal = The Journal of Antibiotics | volume = 28 | issue = 10 | pages = 721–6 | date = Oct 1975 | pmid = 1102508 | doi = 10.7164/antibiotics.28.721 }}</ref> Rapamycin will bind to cytosolic FKBP12 and act as a [[scaffold]] molecule, allowing this protein to dock on the FRB regulatory region (FKBP12-Rapamycin Binding region/domain) on mTORC1.<ref name="pmid17275731">{{cite journal | vauthors = Tsang CK, Qi H, Liu LF, Zheng XF | title = Targeting mammalian target of rapamycin (mTOR) for health and diseases | journal = Drug Discovery Today | volume = 12 | issue = 3–4 | pages = 112–24 | date = Feb 2007 | pmid = 17275731 | doi = 10.1016/j.drudis.2006.12.008 }}</ref> The binding of the FKBP12-rapamycin complex to the FRB regulatory region inhibits mTORC1 through processes not yet known. [[mTORC2]] is also inhibited by rapamycin in some cell culture lines and tissues, particularly those that express high levels of FKBP12 and low levels of FKBP51.<ref>{{Cite journal|title = Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB|journal = Molecular Cell|date = 2006-04-21|issn = 1097-2765|pmid = 16603397|pages = 159–168|volume = 22|issue = 2|doi = 10.1016/j.molcel.2006.03.029|first = Dos D.|last = Sarbassov|first2 = Siraj M.|last2 = Ali|first3 = Shomit|last3 = Sengupta|first4 = Joon-Ho|last4 = Sheen|first5 = Peggy P.|last5 = Hsu|first6 = Alex F.|last6 = Bagley|first7 = Andrew L.|last7 = Markhard|first8 = David M.|last8 = Sabatini}}</ref><ref>{{Cite journal|title = Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity|journal = Science|date = 2012-03-30|issn = 1095-9203|pmc = 3324089|pmid = 22461615|pages = 1638–1643|volume = 335|issue = 6076|doi = 10.1126/science.1215135|first = Dudley W.|last = Lamming|first2 = Lan|last2 = Ye|first3 = Pekka|last3 = Katajisto|first4 = Marcus D.|last4 = Goncalves|first5 = Maki|last5 = Saitoh|first6 = Deanna M.|last6 = Stevens|first7 = James G.|last7 = Davis|first8 = Adam B.|last8 = Salmon|first9 = Arlan|last9 = Richardson}}</ref><ref>{{Cite journal|title = Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins|journal = Aging Cell|date = 2015-04-01|issn = 1474-9726|pmc = 4364838|pmid = 25652038|pages = 265–273|volume = 14|issue = 2|doi = 10.1111/acel.12313|first = Katherine H.|last = Schreiber|first2 = Denise|last2 = Ortiz|first3 = Emmeline C.|last3 = Academia|first4 = Arieanna C.|last4 = Anies|first5 = Chen-Yu|last5 = Liao|first6 = Brian K.|last6 = Kennedy}}</ref>

Rapamycin itself is not very [[water soluble]] and is not very stable, so scientists developed rapamycin analogs, called rapalogs, to overcome these two problems with rapamycin.<ref name="pmid21216931">{{cite journal | vauthors = Vilar E, Perez-Garcia J, Tabernero J | title = Pushing the envelope in the mTOR pathway: the second generation of inhibitors | journal = Molecular Cancer Therapeutics | volume = 10 | issue = 3 | pages = 395–403 | date = Mar 2011 | pmid = 21216931 | pmc = 3413411 | doi = 10.1158/1535-7163.MCT-10-0905 }}</ref> These drugs are considered the first generation inhibitors of mTOR.<ref name="pmid23352077">{{cite journal | vauthors = De P, Miskimins K, Dey N, Leyland-Jones B | title = Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: old targets new hope | journal = Cancer Treatment Reviews | volume = 39 | issue = 5 | pages = 403–12 | date = Aug 2013 | pmid = 23352077 | doi = 10.1016/j.ctrv.2012.12.002 }}</ref> These other inhibitors include [[everolimus]] and [[temsirolimus]].

[[Sirolimus]], which is the drug name for rapamycin, was approved by the U.S. [[Food and Drug Administration]] (FDA) in 1999 to prevent against [[transplant rejection]] in patients undergoing [[kidney transplantation]].<ref name="pmid22941182">{{cite journal | vauthors = Nashan B, Citterio F | title = Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature | journal = Transplantation | volume = 94 | issue = 6 | pages = 547–61 | date = Sep 2012 | pmid = 22941182 | doi = 10.1097/TP.0b013e3182551021 }}</ref> In 2003, it was approved as a [[stent]] covering for people who want to widen their arteries to prevent against future [[heart attacks]].<ref name="pmid22910420">{{cite journal | vauthors = Townsend JC, Rideout P, Steinberg DH | title = Everolimus-eluting stents in interventional cardiology | journal = Vascular Health and Risk Management | volume = 8 | issue =  | pages = 393–404 | year = 2012 | pmid = 22910420 | pmc = 3402052 | doi = 10.2147/VHRM.S23388 }}</ref> In 2007, mTORC1 inhibitors began being approved for treatments against cancers such as [[renal cell carcinoma]].<ref name="pmid21763970">{{cite journal | vauthors = Voss MH, Molina AM, Motzer RJ | title = mTOR inhibitors in advanced renal cell carcinoma | journal = Hematology/oncology Clinics of North America | volume = 25 | issue = 4 | pages = 835–52 | date = Aug 2011 | pmid = 21763970 | pmc = 3587783 | doi = 10.1016/j.hoc.2011.04.008 }}</ref> In 2008 they were approved for treatment of [[mantle cell lymphoma]].<ref name="pmid22687453">{{cite journal | vauthors = Smith SM | title = Targeting mTOR in mantle cell lymphoma: current and future directions | journal = Best Practice & Research. Clinical Haematology | volume = 25 | issue = 2 | pages = 175–83 | date = Jun 2012 | pmid = 22687453 | doi = 10.1016/j.beha.2012.04.008 }}</ref> mTORC1 inhibitors have recently been approved for treatment of [[pancreatic cancer]].<ref name="pmid22475451">{{cite journal | vauthors = Fasolo A, Sessa C | title = Targeting mTOR pathways in human malignancies | journal = Current Pharmaceutical Design | volume = 18 | issue = 19 | pages = 2766–77 | year = 2012 | pmid = 22475451 | doi = 10.2174/138161212800626210 }}</ref> In 2010 they were approved for treatment of [[tuberous sclerosis]].<ref name="pmid22130643">{{cite journal | vauthors = Budde K, Gaedeke J | title = Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition | journal = American Journal of Kidney Diseases | volume = 59 | issue = 2 | pages = 276–83 | date = Feb 2012 | pmid = 22130643 | doi = 10.1053/j.ajkd.2011.10.013 }}</ref>

=== Second generation inhibitors ===

The second generation of inhibitors were created to overcome problems with upstream signaling upon the introduction of first generation inhibitors to the treated cells.<ref name="pmid21333749">{{cite journal | vauthors = Zhang YJ, Duan Y, Zheng XF | title = Targeting the mTOR kinase domain: the second generation of mTOR inhibitors | journal = Drug Discovery Today | volume = 16 | issue = 7–8 | pages = 325–31 | date = Apr 2011 | pmid = 21333749 | pmc = 3073023 | doi = 10.1016/j.drudis.2011.02.008 }}</ref> One problem with the first generation inhibitors of mTORC1 is that there is a [[negative feedback loop]] from phosphorylated S6K, that can inhibit the insulin [[receptor tyrosine kinase|RTK]] via phosphorylation.<ref name="pmid20203102">{{cite journal | vauthors = Veilleux A, Houde VP, Bellmann K, Marette A | title = Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes | journal = Molecular Endocrinology (Baltimore, Md.) | volume = 24 | issue = 4 | pages = 766–78 | date = Apr 2010 | pmid = 20203102 | doi = 10.1210/me.2009-0328 }}</ref> When this negative feedback loop is no longer there, the upstream regulators of mTORC1 become more active than they would otherwise would have been under normal mTORC1 activity. Another problem is that since [[mTORC2]] is resistant to rapamycin, and it too acts upstream of mTORC1 by activating Akt.<ref name="pmid21216931" /> Thus signaling upstream of mTORC1 still remains very active upon its inhibition via rapamycin and the rapalogs.

Second generation inhibitors are able to bind to the [[ATP-binding motif]] on the kinase domain of the mTOR core protein itself and abolish activity of both mTOR complexes.<ref name="pmid21333749" /> In addition, since the mTOR and the PI3K proteins are both in the same [[phosphatidylinositol 3-kinase-related kinase]] (PIKK) family of kinases, some second generation inhibitors have dual inhibition towards the mTOR complexes as well as PI3K, which acts upstream of mTORC1.<ref name="pmid21216931" /> As of 2011, these second generation inhibitors were in [[phases of clinical research|phase II]] of [[clinical trials]].

There have been over 1,300 clinical trials conducted with mTOR inhibitors since 1970.<ref name="pmid23325216">{{cite journal | vauthors = Johnson SC, Rabinovitch PS, Kaeberlein M | title = mTOR is a key modulator of ageing and age-related disease | journal = Nature | volume = 493 | issue = 7432 | pages = 338–45 | date = Jan 2013 | pmid = 23325216 | pmc = 3687363 | doi = 10.1038/nature11861 }}</ref>

== References ==
{{Reflist|35em}}

== External links ==
*{{MeshName|mTORC1+complex,+human}}

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[[Category:Protein complexes]]
[[Category:EC 2.7.11]]
[[Category:Tor signaling pathway]]
[[Category:Human proteins]]