Biology:mTORC2

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Short description: Protein complex

mTOR
Identifiers
SymbolMTOR
Alt. symbolsFRAP, FRAP2, FRAP1
NCBI gene2475
HGNC3942
OMIM601231
RefSeqNM_004958
UniProtP42345
Other data
EC number2.7.11.1
LocusChr. 1 p36
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
MAPKAP1
Identifiers
SymbolMAPKAP1
NCBI gene79109
HGNC18752
OMIM610558
RefSeqNM_001006617.1
UniProtQ9BPZ7
Other data
LocusChr. 9 q34.11

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. ↑ 1.0 1.1 1.2 "mTOR Signaling in Growth, Metabolism, and Disease". Cell 168 (6): 960–976. March 2017. doi:10.1016/j.cell.2017.02.004. PMID 28283069. 
  2. ↑ "mTOR signaling in growth control and disease". Cell 149 (2): 274–93. April 2012. doi:10.1016/j.cell.2012.03.017. PMID 22500797. 
  3. ↑ "Cryo-EM structure of human mTOR complex 2". Cell Research 28 (5): 518–528. May 2018. doi:10.1038/s41422-018-0029-3. PMID 29567957. 
  4. ↑ "The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation". Trends in Biochemical Sciences 36 (6): 320–8. June 2011. doi:10.1016/j.tibs.2011.03.006. PMID 21531565. 
  5. ↑ "Growing knowledge of the mTOR signaling network". Seminars in Cell & Developmental Biology 36: 79–90. December 2014. doi:10.1016/j.semcdb.2014.09.011. PMID 25242279. 
  6. ↑ 6.0 6.1 "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. July 2013. doi:10.1073/pnas.1302455110. PMID 23852728. 
  7. ↑ "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. July 2004. doi:10.1016/j.cub.2004.06.054. PMID 15268862. 
  8. ↑ 8.0 8.1 "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science 307 (5712): 1098–101. February 2005. doi:10.1126/science.1106148. PMID 15718470. Bibcode: 2005Sci...307.1098S. 
  9. ↑ "Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B". Science 279 (5351): 710–4. January 1998. doi:10.1126/science.279.5351.710. PMID 9445477. Bibcode: 1998Sci...279..710S. 
  10. ↑ "Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells". International Journal of Cancer 119 (4): 757–64. August 2006. doi:10.1002/ijc.21932. PMID 16550606. 
  11. ↑ "Mammalian autophagy: core molecular machinery and signaling regulation". Current Opinion in Cell Biology 22 (2): 124–31. April 2010. doi:10.1016/j.ceb.2009.11.014. PMID 20034776. 
  12. ↑ 12.0 12.1 12.2 "mTORC2: The other mTOR in autophagy regulation". Aging Cell 20 (8): e13431. August 2021. doi:10.1111/acel.13431. PMID 34250734. 
  13. ↑ 13.0 13.1 "mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection". Virology 452–453 (March 2014): 175–190. March 2014. doi:10.1016/j.virol.2014.01.008. PMID 24606695. 
  14. ↑ "Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy". Molecular Cell 59 (2): 270–84. July 2015. doi:10.1016/j.molcel.2015.05.030. PMID 26118642. 
  15. ↑ "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. January 2016. doi:10.1038/cr.2015.133. PMID 26584640. 
  16. ↑ "mTOR: from growth signal integration to cancer, diabetes and ageing". Nature Reviews. Molecular Cell Biology 12 (1): 21–35. January 2011. doi:10.1038/nrm3025. PMID 21157483. 
  17. ↑ "Localization of mTORC2 activity inside cells". The Journal of Cell Biology 216 (2): 343–353. February 2017. doi:10.1083/jcb.201610060. PMID 28143890. 
  18. ↑ 18.0 18.1 "mTOR complexes in neurodevelopmental and neuropsychiatric disorders". Nature Neuroscience 16 (11): 1537–1543. 2013. doi:10.1038/nn.3546. PMID 24165680. 
  19. ↑ "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s". Current Biology 16 (18): 1865–70. September 2006. doi:10.1016/j.cub.2006.08.001. PMID 16919458. 
  20. ↑ "mTOR in Brain Physiology and Pathologies". Physiological Reviews 95 (4): 1157–1187. 2015. doi:10.1152/physrev.00038.2014. PMID 26269525. 
  21. ↑ "Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB". Molecular Cell 22 (2): 159–68. April 2006. doi:10.1016/j.molcel.2006.03.029. PMID 16603397. 
  22. ↑ "mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice". Cancer Cell 15 (2): 148–59. February 2009. doi:10.1016/j.ccr.2008.12.017. PMID 19185849. 
  23. ↑ "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity". Science 335 (6076): 1638–43. March 2012. doi:10.1126/science.1215135. PMID 22461615. Bibcode: 2012Sci...335.1638L. 
  24. ↑ "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. October 2010. doi:10.1021/jm101144f. PMID 20860370. 
  25. ↑ "PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex". Cancer Discovery 5 (11): 1194–209. November 2015. doi:10.1158/2159-8290.CD-15-0460. PMID 26293922. 
  26. ↑ "A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation". Cell Reports 12 (6): 937–43. August 2015. doi:10.1016/j.celrep.2015.07.016. PMID 26235620. 
  27. ↑ "The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling". Science 332 (6035): 1317–22. June 2011. doi:10.1126/science.1199498. PMID 21659604. Bibcode: 2011Sci...332.1317H. 
  28. ↑ "Depletion of Ric-8B leads to reduced mTORC2 activity". PLOS Genetics 16 (5): e1008255. May 2020. doi:10.1371/journal.pgen.1008255. PMID 32392211. 
  29. ↑ "Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes". Proceedings of the National Academy of Sciences of the United States of America 111 (49): 17450–5. December 2014. doi:10.1073/pnas.1410530111. PMID 25422441. Bibcode: 2014PNAS..11117450M. 
  30. ↑ "Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling". Proceedings of the National Academy of Sciences of the United States of America 109 (5): 1667–72. January 2012. doi:10.1073/pnas.1110730109. PMID 22307628. Bibcode: 2012PNAS..109.1667Z. 
  31. ↑ "mTORC2 signaling promotes skeletal growth and bone formation in mice". Journal of Bone and Mineral Research 30 (2): 369–78. February 2015. doi:10.1002/jbmr.2348. PMID 25196701. 
  32. ↑ "mTORC2 targets AGC kinases through Sin1-dependent recruitment". The Biochemical Journal 439 (2): 287–97. October 2011. doi:10.1042/BJ20110678. PMID 21806543. https://hal.archives-ouvertes.fr/hal-00628674/file/PEER_stage2_10.1042%252FBJ20110678.pdf. 
  33. ↑ "PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12". Nature Cell Biology 14 (7): 686–96. May 2012. doi:10.1038/ncb2507. PMID 22609986. 
  34. ↑ "Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects". Advances in Biological Regulation 64: 39–48. May 2017. doi:10.1016/j.jbior.2016.12.001. PMID 28189457. 
  35. ↑ "mTORC1 and mTORC2 as regulators of cell metabolism in immunity". FEBS Letters 591 (19): 3089–3103. October 2017. doi:10.1002/1873-3468.12711. PMID 28600802. 
  36. ↑ "mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc". Cell Metabolism 18 (5): 726–39. November 2013. doi:10.1016/j.cmet.2013.09.013. PMID 24140020. 
  37. ↑ "Weighing In on mTOR Complex 2 Signaling: The Expanding Role in Cell Metabolism". Oxidative Medicine and Cellular Longevity 2018: 7838647. 2018-10-30. doi:10.1155/2018/7838647. PMID 30510625. 
  38. ↑ "A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity". Cancer Discovery 4 (5): 554–63. May 2014. doi:10.1158/2159-8290.CD-13-0929. PMID 24631838. 
  39. ↑ "mTORC2 in the center of cancer metabolic reprogramming". Trends in Endocrinology and Metabolism 25 (7): 364–73. July 2014. doi:10.1016/j.tem.2014.04.002. PMID 24856037. 
  40. ↑ "mTORC2 Promotes Tumorigenesis via Lipid Synthesis". Cancer Cell 32 (6): 807–823.e12. December 2017. doi:10.1016/j.ccell.2017.11.011. PMID 29232555. 
  41. ↑ "New Insights for nicotinamide: Metabolic disease, autophagy, and mTOR". Frontiers in Bioscience 25 (11): 1925–1973. June 2020. doi:10.2741/4886. PMID 32472766. 
  42. ↑ "Lifespan extension without fertility reduction following dietary addition of the autophagy activator Torin1 in Drosophila melanogaster". PLOS ONE 13 (1): e0190105. 2018-01-12. doi:10.1371/journal.pone.0190105. PMID 29329306. Bibcode: 2018PLoSO..1390105M. 
  43. ↑ "Haploinsufficiency of akt1 prolongs the lifespan of mice". PLOS ONE 8 (7): e69178. 2013-07-30. doi:10.1371/journal.pone.0069178. PMID 23935948. Bibcode: 2013PLoSO...869178N. 
  44. ↑ "A critical role for the mTORC2 pathway in lung fibrosis". PLOS ONE 9 (8): e106155. 2014-08-27. doi:10.1371/journal.pone.0106155. PMID 25162417. Bibcode: 2014PLoSO...9j6155C. 
  45. ↑ "mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a". Journal of Immunology 201 (2): 371–382. July 2018. doi:10.4049/jimmunol.1701712. PMID 29866702. 
  46. ↑ "Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c". Cell Metabolism 15 (5): 725–38. May 2012. doi:10.1016/j.cmet.2012.03.015. PMID 22521878. 
  47. ↑ "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. August 2012. doi:10.1074/jbc.M112.386854. PMID 22773877. 
  48. ↑ "Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2)". FASEB Journal 28 (1): 300–15. January 2014. doi:10.1096/fj.13-237743. PMID 24072782. 
  49. ↑ "Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan". Aging Cell 13 (5): 911–7. October 2014. doi:10.1111/acel.12256. PMID 25059582. 
  50. ↑ "Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging". eLife 9: e56177. 2020-07-28. doi:10.7554/eLife.56177. PMID 32720643. 
  51. ↑ "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. June 2009. doi:10.1073/pnas.0811321106. PMID 19497867. Bibcode: 2009PNAS..106.9902C. 
  52. ↑ "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. June 2010. doi:10.2337/db09-1061. PMID 20332342. 
  53. ↑ "Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity". Molecular and Cellular Biology 28 (1): 61–70. January 2008. doi:10.1128/MCB.01405-07. PMID 17967879. 
  54. ↑ "Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo". Molecular Metabolism 3 (6): 630–41. September 2014. doi:10.1016/j.molmet.2014.06.004. PMID 25161886. 
  55. ↑ "The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging". Cell Metabolism 23 (6): 990–1003. June 2016. doi:10.1016/j.cmet.2016.05.009. PMID 27304501. 
  56. ↑ "Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size". Diabetes 60 (3): 827–37. March 2011. doi:10.2337/db10-1194. PMID 21266327. 
  57. ↑ "Hypothalamic mTORC2 is essential for metabolic health and longevity". Aging Cell 18 (5): e13014. October 2019. doi:10.1111/acel.13014. PMID 31373126. 

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