mTOR
Identifiers
SymbolMTOR
Alt. symbolsFRAP, FRAP2, FRAP1
NCBI gene2475
HGNC3942
OMIM601231
RefSeqNM_004958
UniProtP42345
Other data
EC number2.7.11.1
LocusChr. 1 p36
Search for
StructuresSwiss-model
DomainsInterPro
RICTOR
Identifiers
SymbolRICTOR
NCBI gene253260
HGNC28611
RefSeqNM_152756
Other data
LocusChr. 5 p13.1
MLST8
Identifiers
SymbolMLST8
NCBI gene64223
HGNC24825
OMIM612190
RefSeqNM_022372
UniProtQ9BVC4
Other data
LocusChr. 16 p13.3
Search for
StructuresSwiss-model
DomainsInterPro
MAPKAP1
Identifiers
SymbolMAPKAP1
NCBI gene79109
HGNC18752
OMIM610558
RefSeqNM_001006617.1
UniProtQ9BPZ7
Other data
LocusChr. 9 q34.11
Search for
StructuresSwiss-model
DomainsInterPro

mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling.[1] The complex itself is rather large, consisting of seven protein subunits. The catalytic mTOR subunit, DEP domain containing mTOR-interacting protein (DEPTOR), mammalian lethal with sec-13 protein 8 (mLST8, also known as GβL), and TTI1/TEL2 complex are shared by both mTORC2 and mTORC1. Rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase interacting protein 1 (mSIN1), and protein observed with rictor 1 and 2 (Protor1/2) can only be found in mTORC2.[2][3] Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.[4]

Function

Though less understood than mTORC1, mTORC2 has been shown to respond to growth factors and to modulate cell metabolism and cell survival, thanks to its activation of the survival kinase Akt.[5] mTORC2 activation by growth factors is done through promotion of mTORC2-ribosome association in PI3K-dependent manner.[6] The complex also plays a role as an important regulator in the organization of the actin cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα).[7]

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.[8][9] Curcumin inhibits both by preventing phosphorylation of the serine.[10] Moreover, mTORC2 activity has been implicated in the regulation of autophagy[11][12](macroautophagy[13] and chaperone-mediated autophagy).[14] 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.[15]

The precise localization of mTORC2 inside cells is still unclear. Some findings based on its activity point to cellular endomembranes, such as of mitochondria, as a possible site of mTORC2,[6] whereas other suggest that the complex could be additionally located at the plasma membrane; however, this may be due to its association with Akt.[16] It is not clear if these membranes display mTORC2 activity in the cellular context, or if these pools contribute to phosphorylation of mTORC2 substrates.[17]

In neurons, mTORC2 facilitates actin polymerization.[18] Mice with reduced mTORC2 have deficient synaptic plasticity and memory.[18]

Regulation and signaling

mTORC2 appears to be regulated by insulin, growth factors, and serum.[19] In contrast to TORC1, which is mainly stimulated by nutrients, TORC2 is mainly stimulated by growth factors.[20] Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.[8] 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.[21] 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.[22][23] Torin-1 can also be used to inhibit mTORC2.[13][24]

Upstream signaling

Similar to other PI3K regulated proteins, mTORC2 has a mSin1 subunit, which contains a phosphoinositide-binding PH domain. This domain is vital for the insulin-dependent regulation of mTORC2 activity and inhibits the catalytic activity of mTORC2 in the absence of insulin. This autoinhibition is relieved upon binding to PI3K-generated PIP3 at the plasma membrane. mSin1 subunit can also be phosphorylated by Akt. This indicates the existence of a positive feedback loop in which partial activation of Akt stimulates the activation of mTORC2. The complex then phosphorylates and fully activates Akt.[1][25][26]

What might come as a surprise is that mTORC2 signaling is also regulated by mTORC1. This is due to the presence of a negative feedback loop between mTORC1 and insulin/PI3K signaling. Grb10, a negative regulator of insulin/IGF-1 receptor signaling upstream of Akt and mTORC2, is phosphorylated and therefore activated by mTORC1.[27] Additionally, some components of G protein signalling has been revealed as important regulators of mTORC2 activity as Ric-8B protein and some lipid metabolites.[28][29][30]

Downstream signaling

mTORC2 controls cell survival and proliferation mainly through phosphorylation of several members of the AGC (PKA/PKG/PKC) protein kinase family. mTORC2 regulates actin cytoskeleton through PKCα [31] but is able to phosphorylate other members of the PKC family that have various regulatory functions in cell migration and cytoskeletal remodeling.[32][33] mTORC2 plays a pivotal role in phosphorylation and thus in activation of Akt, which is a vital signaling component downstream from PI3K once active,[34] and also in phosphorylation of SGK1, PKC [35] and HDACs.[36][12]

Role in disease

Since mTORC2 plays a crucial role in metabolic regulation, it can be linked to many human pathologies. Deregulation of mTOR signaling, including mTORC2, affects transduction of insulin signal and therefore can disrupt its biological functions and lead to metabolic disorders, such as type 2 diabetes mellitus.[37] In many types of human cancer, hyperactivation of mTORC2 caused by mutations and aberrant amplifications of mTORC2 core components is frequently observed.[38] On metabolic level, activation of mTORC2 stimulates processes related to alteration of glucose metabolism in cancer cells, altogether known as Warburg effect.[39] mTORC2-mediated lipogenesis has been linked to promotion of hepatocellular carcinoma through stimulation of glycerophospholipid and sphingolipid synthesis.[40]

Although mTORC2 is acutely insensitive to rapamycin, chronic rapamycin treatment abrogates mTORC2 signaling, leading to insulin resistance and glucose intolerance.[1][41][12] By contrast, dietary administration of Torin1, a dual mTORC1/2 inhibitor, resulted in prolonged lifespan in D. melanogaster with no reduction in fertility [42] and Akt haploinsufficiency, an mTORC2 downstream target, extended lifespan in mice.[43]

The mTORC2 pathways plays a crucial role in pathogenesis of lung fibrosis, and inhibitors of its active site such as sapanisertib (MLN-0128) have potential in the treatment of this disease and similar fibrotic lung diseases.[44]

Chronic mTORC2 activity may play a role in systemic lupus erythematosus by impairing lysosome function.[45]

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.[46][47][48][49][50] Adipose-specific disruption of mTORC2 through deletion of Rictor may protect from a high-fat diet in young mice,[51] but results in hepatic steatosis and insulin resistance in older mice.[52] 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.[53][54][55] Loss of mTORC2/Rictor in pancreatic beta cells results in reduced beta cell mass and insulin secretion, and hyperglycemia and glucose intolerance.[56] mTORC2 activity in the hypothalamus of mice increases with age, and deletion of Rictor in hypothalamic neurons promotes obesity, frailty, and shorter lifespan in mice.[57]

References

  1. 1 2 3 Saxton RA, Sabatini DM (March 2017). "mTOR Signaling in Growth, Metabolism, and Disease". Cell. 168 (6): 960–976. doi:10.1016/j.cell.2017.02.004. PMC 5394987. PMID 28283069.
  2. ↑ Laplante M, Sabatini DM (April 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.
  3. ↑ Chen X, Liu M, Tian Y, Li J, Qi Y, Zhao D, et al. (May 2018). "Cryo-EM structure of human mTOR complex 2". Cell Research. 28 (5): 518–528. doi:10.1038/s41422-018-0029-3. PMC 5951902. PMID 29567957.
  4. ↑ Mendoza MC, Er EE, Blenis J (June 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.
  5. ↑ Huang K, Fingar DC (December 2014). "Growing knowledge of the mTOR signaling network". Seminars in Cell & Developmental Biology. 36: 79–90. doi:10.1016/j.semcdb.2014.09.011. PMC 4253687. PMID 25242279.
  6. 1 2 Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall MN (July 2013). "Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology". Proceedings of the National Academy of Sciences of the United States of America. 110 (31): 12526–34. doi:10.1073/pnas.1302455110. PMC 3732980. PMID 23852728.
  7. ↑ Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. (July 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. S2CID 4658268.
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  10. ↑ Beevers CS, Li F, Liu L, Huang S (August 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. S2CID 25454463.
  11. ↑ Yang Z, Klionsky DJ (April 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.
  12. 1 2 3 Ballesteros-Álvarez J, Andersen JK (August 2021). "mTORC2: The other mTOR in autophagy regulation". Aging Cell. 20 (8): e13431. doi:10.1111/acel.13431. PMC 8373318. PMID 34250734.
  13. 1 2 Datan E, Shirazian A, Benjamin S, Matassov D, Tinari A, Malorni W, et al. (March 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.
  14. ↑ Arias E, Koga H, Diaz A, Mocholi E, Patel B, Cuervo AM (July 2015). "Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy". Molecular Cell. 59 (2): 270–84. doi:10.1016/j.molcel.2015.05.030. PMC 4506737. PMID 26118642.
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  17. ↑ Ebner M, Sinkovics B, Szczygieł M, Ribeiro DW, Yudushkin I (February 2017). "Localization of mTORC2 activity inside cells". The Journal of Cell Biology. 216 (2): 343–353. doi:10.1083/jcb.201610060. PMC 5294791. PMID 28143890.
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  33. ↑ Gan X, Wang J, Wang C, Sommer E, Kozasa T, Srinivasula S, et al. (May 2012). "PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12". Nature Cell Biology. 14 (7): 686–96. doi:10.1038/ncb2507. PMC 3389271. PMID 22609986.
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  38. ↑ Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, et al. (May 2014). "A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity". Cancer Discovery. 4 (5): 554–63. doi:10.1158/2159-8290.CD-13-0929. PMC 4012430. PMID 24631838.
  39. ↑ Masui K, Cavenee WK, Mischel PS (July 2014). "mTORC2 in the center of cancer metabolic reprogramming". Trends in Endocrinology and Metabolism. 25 (7): 364–73. doi:10.1016/j.tem.2014.04.002. PMC 4077930. PMID 24856037.
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  42. ↑ Mason JS, Wileman T, Chapman T (2018-01-12). "Lifespan extension without fertility reduction following dietary addition of the autophagy activator Torin1 in Drosophila melanogaster". PLOS ONE. 13 (1): e0190105. Bibcode:2018PLoSO..1390105M. doi:10.1371/journal.pone.0190105. PMC 5766080. PMID 29329306.
  43. ↑ Nojima A, Yamashita M, Yoshida Y, Shimizu I, Ichimiya H, Kamimura N, et al. (2013-07-30). Sadoshima J (ed.). "Haploinsufficiency of akt1 prolongs the lifespan of mice". PLOS ONE. 8 (7): e69178. Bibcode:2013PLoSO...869178N. doi:10.1371/journal.pone.0069178. PMC 3728301. PMID 23935948.
  44. ↑ Chang W, Wei K, Ho L, Berry GJ, Jacobs SS, Chang CH, Rosen GD (2014-08-27). Mora A (ed.). "A critical role for the mTORC2 pathway in lung fibrosis". PLOS ONE. 9 (8): e106155. Bibcode:2014PLoSO...9j6155C. doi:10.1371/journal.pone.0106155. PMC 4146613. PMID 25162417.
  45. ↑ Monteith AJ, Vincent HA, Kang S, Li P, Claiborne TM, Rajfur Z, et al. (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. PMC 6039264. PMID 29866702.
  46. ↑ Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, et al. (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.
  47. ↑ Yuan M, Pino E, Wu L, Kacergis M, Soukas AA (August 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.
  48. ↑ Lamming DW, Demirkan G, Boylan JM, Mihaylova MM, Peng T, Ferreira J, et al. (January 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.
  49. ↑ Lamming DW, Mihaylova MM, Katajisto P, Baar EL, Yilmaz OH, Hutchins A, et al. (October 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.
  50. ↑ Arriola Apelo SI, Lin A, Brinkman JA, Meyer E, Morrison M, Tomasiewicz JL, et al. (2020-07-28). "Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging". eLife. 9: e56177. doi:10.7554/eLife.56177. PMC 7386906. PMID 32720643.
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  55. ↑ 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.
  56. ↑ Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA (March 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.
  57. ↑ Chellappa K, Brinkman JA, Mukherjee S, Morrison M, Alotaibi MI, Carbajal KA, et al. (October 2019). "Hypothalamic mTORC2 is essential for metabolic health and longevity". Aging Cell. 18 (5): e13014. doi:10.1111/acel.13014. PMC 6718533. PMID 31373126.
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