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Alt. symbolsFRAP, FRAP2, FRAP1
Other data
EC number2.7.11.1
LocusChr. 1 p36
Other data
LocusChr. 5 p13.1
Other data
LocusChr. 16 p13.3
Other data
LocusChr. 9 q34.11

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 GβL, mammalian stress-activated protein kinase interacting protein 1 (mSIN1), as well as Protor 1/2, DEPTOR, and TTI1 and TEL2.[1][2][3]


mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα).[2]

mTORC2 also regulates cellular proliferation and metabolism, in part through the regulation of IGF-IR, InsR, Akt/PKB and the serum-and glucocorticoid-induced protein kinase SGK. mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue S473 as well as serine residue S450. Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation.[4][5] Curcumin inhibits both by preventing phosphorylation of the serine.[6] Moreover, mTORC2 activity has been implicated in the regulation of autophagy[7](macroautophagy[8] and chaperone mediated autophagy).[9] 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.[10]


mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels.[1] Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.[4] 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.[11] 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.[12][13] Torin1 can also be used to inhibit mTORC2.[8][14]

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.[15]

mTORC2 activation has thought to be due to growth factors, given that it regulates the activity of Akt and PKC.[4]

mTORC2 may play a role in cancer, given its regulation of the widely studied oncogenetic Akt pathway.[12] Chronic mTORC2 activity may play a role in systemic lupus erythematosus by impairing lysosome function[16].

Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.[17]

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.[18][19][20][21] Adipose-specific disruption of mTORC2 through deletion of Rictor may protect from a high-fat diet in young mice,[22] but results in hepatic steatosis and insulin resistance in older mice.[23] 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.[24][25][26] Loss of mTORC2/Rictor in pancreatic beta cells results in reduced beta cell mass and insulin secretion, and hyperglycemia and glucose intolerance.[27]


  1. 1.0 1.1 Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM (Sep 2006). "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s". Current Biology. 16 (18): 1865–70. doi:10.1016/j.cub.2006.08.001. PMID 16919458.
  2. 2.0 2.1 Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (Jul 2004). "Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton". Current Biology. 14 (14): 1296–302. doi:10.1016/j.cub.2004.06.054. PMID 15268862.
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  4. 4.0 4.1 4.2 Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (Feb 2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science. 307 (5712): 1098–101. doi:10.1126/science.1106148. PMID 15718470.
  5. 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 (Jan 1998). "Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B". Science. 279 (5351): 710–4. doi:10.1126/science.279.5351.710. PMID 9445477.
  6. Beevers CS, Li F, Liu L, Huang S (Aug 2006). "Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells". International Journal of Cancer. 119 (4): 757–64. doi:10.1002/ijc.21932. PMID 16550606.
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  12. 12.0 12.1 Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM (February 2009). "mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice". Cancer Cell. 15 (2): 148–59. doi:10.1016/j.ccr.2008.12.017. PMC 2701381. PMID 19185849.
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  14. Liu Q, Chang JW, Wang J, Kang SA, Thoreen CC, Markhard A, Hur W, Zhang J, Sim T, Sabatini DM, Gray NS (Oct 2010). "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 of Medicinal Chemistry. 53 (19): 7146–55. doi:10.1021/jm101144f. PMC 3893826. PMID 20860370.
  15. Zoncu R, Efeyan A, Sabatini DM (Jan 2011). "mTOR: from growth signal integration to cancer, diabetes and ageing". Nature Reviews Molecular Cell Biology. 12 (1): 21–35. doi:10.1038/nrm3025. PMC 3390257. PMID 21157483.
  16. Monteith AJ, Vincent HA, Kang S, Li P, Claiborne TM, Rajfur Z, Jacobson K, Moorman NJ, Vilen BJ (July 2018). "mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a". Journal of Immunology. 201 (2): 371–382. doi:10.4049/jimmunol.1701712. PMID 29866702.
  17. Mendoza MC, Er EE, Blenis J (Jun 2011). "The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation". Trends in Biochemical Sciences. 36 (6): 320–8. doi:10.1016/j.tibs.2011.03.006. PMC 3112285. PMID 21531565.
  18. Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Rüegg MA, Hall MN (May 2012). "Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c". Cell Metabolism. 15 (5): 725–38. doi:10.1016/j.cmet.2012.03.015. PMID 22521878.
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  22. Cybulski N, Polak P, Auwerx J, Rüegg MA, Hall MN (Jun 2009). "mTOR complex 2 in adipose tissue negatively controls whole-body growth". Proceedings of the National Academy of Sciences of the United States of America. 106 (24): 9902–7. doi:10.1073/pnas.0811321106. PMC 2700987. PMID 19497867.
  23. Kumar A, Lawrence JC, Jung DY, Ko HJ, Keller SR, Kim JK, Magnuson MA, Harris TE (Jun 2010). "Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism". Diabetes. 59 (6): 1397–406. doi:10.2337/db09-1061. PMC 2874700. PMID 20332342.
  24. Kumar A, Harris TE, Keller SR, Choi KM, Magnuson MA, Lawrence JC (January 2008). "Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity". Molecular and Cellular Biology. 28 (1): 61–70. doi:10.1128/MCB.01405-07. PMC 2223287. PMID 17967879.
  25. 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 (September 2014). "Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo". Molecular Metabolism. 3 (6): 630–41. doi:10.1016/j.molmet.2014.06.004. PMC 4142396. PMID 25161886.
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