View source for MTORC2

{{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 = 
}}
{{infobox protein
| Name = [[RICTOR]]
| caption = 
| image = 
| width = 
| HGNCid = 28611
| Symbol = [[RICTOR]]
| AltSymbols = 
| EntrezGene = 253260
| OMIM = 
| RefSeq = NM_152756
| UniProt = 
| PDB = 
| ECnumber = 
| Chromosome = 5
| Arm = p
| Band = 13.1
| LocusSupplementaryData = 
}}
{{infobox protein
| Name = [[MLST8]]
| caption = 
| image = 
| width = 
| HGNCid = 24825
| Symbol = [[MLST8]]
| AltSymbols = 
| EntrezGene = 64223
| OMIM = 612190
| RefSeq = NM_022372
| UniProt = Q9BVC4
| PDB = 
| ECnumber = 
| Chromosome = 16
| Arm = p
| Band = 13.3
| LocusSupplementaryData = 
}}
{{infobox protein
| Name = [[MAPKAP1]]
| caption = 
| image = 
| width = 
| HGNCid = 18752
| Symbol = [[MAPKAP1]]
| AltSymbols = 
| EntrezGene = 79109
| OMIM = 610558
| RefSeq = NM_001006617.1
| UniProt = Q9BPZ7
| PDB = 
| ECnumber = 
| Chromosome = 9
| Arm = q
| Band = 34.11
| LocusSupplementaryData = 
}}
'''mTOR Complex 2''' ('''mTORC2''') is a [[protein complex]] that regulates cellular metabolism as well as the [[cytoskeleton]]. It is defined by the interaction of [[mTOR]] and the rapamycin-insensitive companion of mTOR ([[RICTOR]]), and also includes [[MLST8|GβL]], mammalian stress-activated protein kinase interacting protein 1 ([[MAPKAP1|mSIN1]]), as well as Protor 1/2, [[DEPTOR]], and TTI1 and [[TELO2|TEL2]].<ref name=Frias>{{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 = Sep 2006 | pmid = 16919458 | doi = 10.1016/j.cub.2006.08.001 }}</ref><ref name=Sarb1>{{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 = Jul 2004 | pmid = 15268862 | doi = 10.1016/j.cub.2004.06.054 }}</ref><ref name=Laplante1>{{cite journal | vauthors = Laplante M, Sabatini DM | title = mTOR signaling in growth control and disease | journal = Cell | volume = 149 | issue = 2 | pages = 274–93 | date = Apr 2012 | pmid = 22500797 | pmc = 3331679 | doi = 10.1016/j.cell.2012.03.017 }}</ref>

== Function ==

mTORC2 has been shown to function as an important regulator of the [[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=Sarb1/>

mTORC2 also regulates cellular proliferation and metabolism, in part through the regulation of [[IGF-IR]], [[InsR]], [[AKT|Akt/PKB]] and the serum-and glucocorticoid-induced protein kinase [[SGK]]. mTORC2 phosphorylates the serine/threonine protein kinase [[AKT|Akt/PKB]] at a serine residue S473 as well as serine residue S450<!--serine473-->. Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308<!--threonine308--> residue 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 = Feb 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 = Jan 1998 | pmid = 9445477 | doi = 10.1126/science.279.5351.710 }}</ref> [[Curcumin]] inhibits both by preventing phosphorylation of the serine.<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 = Aug 2006 | pmid = 16550606 | doi = 10.1002/ijc.21932 }}</ref> Moreover, mTORC2 activity has been implicated in the regulation of autophagy<ref>{{cite journal | vauthors = Yang Z, Klionsky DJ | title = Mammalian autophagy: core molecular machinery and signaling regulation | journal = Current Opinion in Cell Biology | volume = 22 | issue = 2 | pages = 124–31 | date = Apr 2010 | pmid = 20034776 | pmc = 2854249 | doi = 10.1016/j.ceb.2009.11.014 }}</ref>(macroautophagy<ref name=Datan>{{cite journal | vauthors = Datan E, Shirazian A, Benjamin S, Matassov D, Tinari A, Malorni W, Lockshin RA, Garcia-Sastre A, Zakeri Z | title = mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection | journal = Virology | volume = 452-453 | issue = March 2014 | pages = 175–90 | date = Mar 2014 | pmid = 24606695 | pmc = 4005847 | doi = 10.1016/j.virol.2014.01.008 }}</ref> and chaperone mediated autophagy).<ref name=Arias>{{cite journal | vauthors = Arias E, Koga H, Diaz A, Mocholi E, Patel B, Cuervo AM | title = Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy | journal = Mol Cell | volume = 59(2) | issue = June 2015 | pages = 270–84 | date = June 2015 | pmid = 26118642 | pmc = 4506737 | doi = 10.1016/j.molcel.2015.05.030 }}</ref> In addition, mTORC2 has tyrosine kinase activity and phosphorylates IGF-IR and insulin receptor at the tyrosine residues Y1131/1136 and Y1146/1151, respectively, leading to full activation of IGF-IR and InsR.<ref name=PMID26584640>{{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 = Jan 2016 | pmid = 26584640 | doi = 10.1038/cr.2015.133 }}</ref>

== Regulation ==

mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels.<ref name=Frias/>  Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.<ref name="pmid15718470"/>  However, subsequent studies have shown that, at least in some cell lines, chronic exposure to rapamycin, while not affecting pre-existing mTORC2s, promotes rapamycin inhibition of free mTOR molecules, thus inhibiting the formation of new mTORC2.<ref name=Sarb3>{{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 = Apr 2006 | pmid = 16603397 | doi = 10.1016/j.molcel.2006.03.029 }}</ref> mTORC2 can be inhibited by chronic treatment with rapamycin ''in vivo'', both in cancer cells and normal tissues such as the liver and adipose tissue.<ref name=pmid19185849 /><ref>{{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 = Mar 2012 | pmid = 22461615 | pmc = 3324089 | doi = 10.1126/science.1215135 }}</ref> Torin1 can also be used to inhibit mTORC2.<ref name="Datan"/><ref name=Liu>{{cite journal | vauthors = Liu Q, Chang JW, Wang J, Kang SA, Thoreen CC, Markhard A, Hur W, Zhang J, Sim T, Sabatini DM, Gray NS | title = Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 19 | pages = 7146–55 | date = Oct 2010 | pmid = 20860370 | pmc = 3893826 | doi = 10.1021/jm101144f }}</ref>

Localization of mTORC2 in the cell has been suggested to be at the plasma membrane; however, this may be due to its association with Akt.<ref name="pmid21157483">{{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 = Jan 2011 | pmid = 21157483 | pmc = 3390257 | doi = 10.1038/nrm3025 }}</ref>

mTORC2 activation has thought to be due to growth factors, given that it regulates the activity of Akt and PKC.<ref name="pmid15718470"/>

mTORC2 may play a role in cancer, given its regulation of the widely studied oncogenetic Akt pathway.<ref name="pmid19185849">{{cite journal | vauthors = Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM | title = mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice | journal = Cancer Cell | volume = 15 | issue = 2 | pages = 148–59 | date = Feb 2009 | pmid = 19185849 | pmc = 2701381 | doi = 10.1016/j.ccr.2008.12.017 }}</ref>

Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.<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>

Studies using mice with tissue-specific loss of ''Rictor'', and thus inactive mTORC2, have found that mTORC2 plays a critical role in the regulation of glucose homeostasis. Liver-specific disruption of mTORC2 through hepatic deletion of the gene ''Rictor'' leads to glucose intolerance, hepatic insulin resistance, decreased hepatic lipogenesis, and decreased male lifespan.<ref>{{cite journal | vauthors = Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Rüegg MA, Hall MN | title = Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c | journal = Cell Metabolism | volume = 15 | issue = 5 | pages = 725–38 | date = May 2012 | pmid = 22521878 | doi = 10.1016/j.cmet.2012.03.015 }}</ref><ref>{{cite journal | vauthors = Yuan M, Pino E, Wu L, Kacergis M, Soukas AA | title = Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2 | journal = The Journal of Biological Chemistry | volume = 287 | issue = 35 | pages = 29579–88 | date = Aug 2012 | pmid = 22773877 | pmc = 3436168 | doi = 10.1074/jbc.M112.386854 }}</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 = Jan 2014 | pmid = 24072782 | pmc = 3868844 | doi = 10.1096/fj.13-237743 }}</ref><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 = Oct 2014 | pmc = 4172536 | doi = 10.1111/acel.12256 | pmid = 25059582 }}</ref> Adipose-specific disruption of mTORC2 through deletion of ''Rictor'' may protect from a high-fat diet in young mice,<ref>{{cite journal | vauthors = Cybulski N, Polak P, Auwerx J, Rüegg MA, Hall MN | title = mTOR complex 2 in adipose tissue negatively controls whole-body growth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 24 | pages = 9902–7 | date = Jun 2009 | pmid = 19497867 | pmc = 2700987 | doi = 10.1073/pnas.0811321106 }}</ref> but results in hepatic steatosis and insulin resistance in older mice.<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 = Jun 2010 | pmid = 20332342 | pmc = 2874700 | doi = 10.2337/db09-1061 }}</ref> The role of mTORC2 in skeletal muscle has taken time to uncover, but genetic loss of mTORC2/''Rictor'' in skeletal muscle results in decreased insulin-stimulated glucose uptake, and resistance to the effects of an mTOR kinase inhibitor on insulin resistance, highlighting a critical role for mTOR in the regulation of glucose homeostasis in this tissue.<ref>{{cite journal | vauthors = Kumar A, Harris TE, Keller SR, Choi KM, Magnuson MA, Lawrence JC | title = Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity | journal = Molecular and Cellular Biology | volume = 28 | issue = 1 | pages = 61–70 | date = January 2008 | pmid = 17967879 | pmc = 2223287 | doi = 10.1128/MCB.01405-07 }}</ref><ref>{{cite journal | vauthors = Kleinert M, Sylow L, Fazakerley DJ, Krycer JR, Thomas KC, Oxbøll AJ, Jordy AB, Jensen TE, Yang G, Schjerling P, Kiens B, James DE, Ruegg MA, Richter EA | title = Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo | journal = Molecular Metabolism | volume = 3 | issue = 6 | pages = 630–41 | date = September 2014 | pmid = 25161886 | pmc = 4142396 | doi = 10.1016/j.molmet.2014.06.004 }}</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> Loss of mTORC2/''Rictor'' in pancreatic beta cells results in reduced beta cell mass and insulin secretion, and hyperglycemia and glucose intolerance.<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 = Mar 2011 | pmid = 21266327 | pmc = 3046843 | doi = 10.2337/db10-1194 }}</ref>

== References ==
{{Reflist|33em}}

== External links ==
*{{MeshName|TOR+complex+2|2012}}}

{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
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[[Category:Protein complexes]]
[[Category:EC 2.7.11]]
[[Category:Tor signaling pathway]]
[[Category:Human proteins]]