mTORC2

mTOR
Identifiers
Symbol MTOR
Alt. symbols FRAP, FRAP2, FRAP1
Entrez 2475
HUGO 3942
OMIM 601231
RefSeq NM_004958
UniProt P42345
Other data
EC number 2.7.11.1
Locus Chr. 1 p36
RICTOR
Identifiers
Symbol RICTOR
Entrez 253260
HUGO 28611
RefSeq NM_152756
Other data
Locus Chr. 5 p13.1
MLST8
Identifiers
Symbol MLST8
Entrez 64223
HUGO 24825
OMIM 612190
RefSeq NM_022372
UniProt Q9BVC4
Other data
Locus Chr. 16 p13.3
mitogen-activated protein kinase associated protein 1
Identifiers
Symbol MAPKAP1
Entrez 79109
HUGO 18752
OMIM 610558
RefSeq NM_001006617.1
UniProt Q9BPZ7
Other data
Locus Chr. 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 metabolism, in part through the regulation of 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][8]

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.[9] 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.[10][11] Torin1 can also be used to inhibit mTORC2.[8][12]

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.[13]

mTORC2 activation has thought to be due to growth factors, given that it regulates the activity of Akt and PKC.[14]

mTORC2 may play a role in cancer, given its regulation of the widely studied oncogenetic Akt pathway.[10]

Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.[15]

References

  1. ↑ 1.0 1.1 Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM (2006). "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s". Curr Biol 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 (2004). "Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton". Curr Biol 14 (14): 1296–302. doi:10.1016/j.cub.2004.06.054. PMID 15268862.
  3. ↑ Laplante M, Sabatini DM (Apr 13, 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 Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (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 (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 (2006). "Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells". Int J 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 (2014). "mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection". Virology. 452-453 (March 2014): 175–190. doi:10.1016/j.virol.2014.01.008. PMC 4005847. PMID 24606695.
  9. ↑ Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006). "Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB". Mol Cell 22 (2): 159–68. doi:10.1016/j.molcel.2006.03.029. PMID 16603397.
  10. ↑ 10.0 10.1 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.
  11. ↑ 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 30, 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.
  12. ↑ Liu Q, Chang JW, Kang SA, Thoreen CC, Markhard A, Hur W, Zhang J, Sim T, Sabatini DM, Gray NS (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". J. Med Chem 53 (19): 7146–7155. doi:10.1021/jm101144f. PMC 3893826. PMID 20860370.
  13. ↑ Zoncu R, Efeyan A, Sabatini DM (January 2011). "mTOR: from growth signal integration to cancer, diabetes and ageing". Nat. Rev. Mol. Cell Biol. 12 (1): 21–35. doi:10.1038/nrm3025. PMC 3390257. PMID 21157483.
  14. ↑ Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (February 2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science 307 (5712): 1098–101. doi:10.1126/science.1106148. PMID 15718470.
  15. ↑ Mendoza MC, Er EE, Blenis J (June 2011). "The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation". Trends Biochem. Sci. 36 (6): 320–8. doi:10.1016/j.tibs.2011.03.006. PMC 3112285. PMID 21531565.

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