mTORC2

Jump to navigation Jump to search

mTOR
Identifiers
SymbolMTOR
Alt. symbolsFRAP, FRAP2, FRAP1
Entrez2475
HUGO3942
OMIM601231
RefSeqNM_004958
UniProtP42345
Other data
EC number2.7.11.1
LocusChr. 1 p36
RICTOR
Identifiers
SymbolRICTOR
Entrez253260
HUGO28611
RefSeqNM_152756
Other data
LocusChr. 5 p13.1
MLST8
Identifiers
SymbolMLST8
Entrez64223
HUGO24825
OMIM612190
RefSeqNM_022372
UniProtQ9BVC4
Other data
LocusChr. 16 p13.3
MAPKAP1
Identifiers
SymbolMAPKAP1
Entrez79109
HUGO18752
OMIM610558
RefSeqNM_001006617.1
UniProtQ9BPZ7
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]

Function

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]

Regulation

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]

References

  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.
  3. ↑ Laplante M, Sabatini DM (Apr 2012). "mTOR signaling in growth control and disease". Cell. 149 (2): 274–93. doi:10.1016/j.cell.2012.03.017. PMC 3331679. PMID 22500797.
  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.
  7. ↑ Yang Z, Klionsky DJ (Apr 2010). "Mammalian autophagy: core molecular machinery and signaling regulation". Current Opinion in Cell Biology. 22 (2): 124–31. doi:10.1016/j.ceb.2009.11.014. PMC 2854249. PMID 20034776.
  8. ↑ 8.0 8.1 Datan E, Shirazian A, Benjamin S, Matassov D, Tinari A, Malorni W, Lockshin RA, Garcia-Sastre A, Zakeri Z (Mar 2014). "mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection". Virology. 452-453 (March 2014): 175–90. doi:10.1016/j.virol.2014.01.008. PMC 4005847. PMID 24606695.
  9. ↑ Arias E, Koga H, Diaz A, Mocholi E, Patel B, Cuervo AM (June 2015). "Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy". Mol Cell. 59 (2): 270–84. doi:10.1016/j.molcel.2015.05.030. PMC 4506737. PMID 26118642.
  10. ↑ Yin Y, Hua H, Li M, Liu S, Kong Q, Shao T, Wang J, Luo Y, Wang Q, Luo T, Jiang Y (Jan 2016). "mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR". Cell Research. 26 (1): 46–65. doi:10.1038/cr.2015.133. PMC 4816127. PMID 26584640.
  11. ↑ Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (Apr 2006). "Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB". Molecular Cell. 22 (2): 159–68. doi:10.1016/j.molcel.2006.03.029. PMID 16603397.
  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.
  13. ↑ 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 (Mar 2012). "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity". Science. 335 (6076): 1638–43. doi:10.1126/science.1215135. PMC 3324089. PMID 22461615.
  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.
  19. ↑ Yuan M, Pino E, Wu L, Kacergis M, Soukas AA (Aug 2012). "Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2". The Journal of Biological Chemistry. 287 (35): 29579–88. doi:10.1074/jbc.M112.386854. PMC 3436168. PMID 22773877.
  20. ↑ Lamming DW, Demirkan G, Boylan JM, Mihaylova MM, Peng T, Ferreira J, Neretti N, Salomon A, Sabatini DM, Gruppuso PA (Jan 2014). "Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2)". FASEB Journal. 28 (1): 300–15. doi:10.1096/fj.13-237743. PMC 3868844. PMID 24072782.
  21. ↑ Lamming DW, Mihaylova MM, Katajisto P, Baar EL, Yilmaz OH, Hutchins A, Gultekin Y, Gaither R, Sabatini DM (Oct 2014). "Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan". Aging Cell. 13 (5): 911–7. doi:10.1111/acel.12256. PMC 4172536. PMID 25059582.
  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.
  26. ↑ Kennedy BK, Lamming DW (June 2016). "The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging". Cell Metabolism. 23 (6): 990–1003. doi:10.1016/j.cmet.2016.05.009. PMC 4910876. PMID 27304501.
  27. ↑ Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA (Mar 2011). "Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size". Diabetes. 60 (3): 827–37. doi:10.2337/db10-1194. PMC 3046843. PMID 21266327.

External links

Retrieved from "https://www.wikidoc.org/index.php?title=MTORC2&oldid=1522685"