THE MTOR KOMPLEKS 2 I NJEGOVA ULOGA U NERVNOM SISTEMU
Ključne reči:
mTORC2, bolesti nervnog sistema
Sažetak
Mehanistička meta rapamicina u sisara (mTOR) je široko eksprimirana multimerna serin/treonin protein kinaza, koja ima važnu ulogu u regulaciji ćelijskog metabolizma, rasta i preživljavanja. mTOR formira dva, evolutivno očuvana, signalna kompleksa: mTOR kompleks 1 i 2 (mTORC i mTORC2). Uloga mTORC1 kao centralnog regulatora rasta i metabolizma je uveliko proučavana, dok su uloge mTORC2 i signali koji regulišu njegovu aktivnost manje ispitivani. Genetske studije su pokazale važnu ulogu mTORC2 za normalnu neuronsku strukturu i funkciju. Takođe, promena aktivnosti mTORC2 signalnog puta je uočena kod nekoliko neurodegenerativnih i neurorazvojnih poremećaja, kao i kod epilepsije. Ovaj pregledni članak daje pregled trenutnog razumevanja mTORC2, uključujući njegove komponente, kao i poznate funkcije u regulaciji različitih ćelijskih procesa i u različitim poremećajima nervnog sistema.
Ključne reči: mTORC2, bolesti nervnog sistema
Reference
References
1. Liu, M., Li, G., Song, X. et al. Prevalence, risk factors, and prognosis of central nervous system manifestations in antiphospholipid syndrome. Sci Rep 13, 8915 (2023).
2. Maiese K. The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk. Front Immunol. 2023 Nov 8;14:1273570.
3. Sanghai N, Tranmer GK. Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View. Cells. 2023;12(18):2318.
4. Kaur A, Sharma S. Mammalian target of rapamycin (mTOR) as a potential therapeutic target in various diseases. Inflammopharmacology. 2017;25(3):293-312.
5. Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014 Oct 22;84(2):275-91.
6. Rabanal-Ruiz Y, Otten EG, Korolchuk VI. mTORC1 as the main gateway to autophagy. Essays Biochem. 2017; 61(6):565-584.
7. Bockaert J, Marin P. mTOR in Brain Physiology and Pathologies. Physiol Rev. 2015;95(4):1157-87.
8. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93.
9. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307(5712):1098-101.
10. Fu W, Hall MN. Regulation of mTORC2 Signaling. Genes (Basel). 2020;11(9):1045.
11. Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall MN. Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proc Natl Acad Sci U S A. 2013;110(31):12526-34.
12. Ebner M, Sinkovics B, Szczygieł M, Ribeiro DW, Yudushkin I. Localization of mTORC2 activity inside cells. J Cell Biol. 2017 Feb;216(2):343-353. Ebner M, Sinkovics B, Szczygieł M, Ribeiro DW, Yudushkin I. Localization of mTORC2 activity inside cells. J Cell Biol. 2017;216(2):343-353.
13. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960-976.
14. Heras-Sandoval D, Pérez-Rojas JM, Pedraza-Chaverri J. Novel compounds for the modulation of mTOR and autophagy to treat neurodegenerative diseases. Cell Signal. 2020; 65:109442.
15. Jaworski J, Sheng M. The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol. 2006;34(3):205-19.
16. Kazyken D, Magnuson B, Bodur C, Acosta-Jaquez HA, Zhang D, Tong X et al. AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. Sci Signal. 2019; 12(585):eaav3249.
17. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296-302.
18. Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, Liu D, Wan L, Zhai B, Yu Y, Yuan M, Kim BM, Shaik S, Menon S, Gygi SP, Lee TH, Asara JM, Manning BD, Blenis J, Su B, Wei W. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol. 2013;15(11):1340-50.
19. Bové J, Martínez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci. 2011;12(8):437-52.
20. Yuan HX, Guan KL. The SIN1-PH Domain Connects mTORC2 to PI3K. Cancer Discov. 2015;5(11):1127-9.
21. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127(1):125-37.
22. Kocalis HE, Hagan SL, George L, Turney MK, Siuta MA, Laryea GN, Morris LC, Muglia LJ, Printz RL, Stanwood GD, Niswender KD. Rictor/mTORC2 facilitates central regulation of energy and glucose homeostasis. Mol Metab. 2014;3(4):394-407.
23. Treins C, Warne PH, Magnuson MA, Pende M, Downward J. Rictor is a novel target of p70 S6 kinase-1. Oncogene. 2010;29(7):1003-16.
24. Laugier F, Finet-Benyair A, André J, Rachakonda PS, Kumar R, Bensussan A, Dumaz N. RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma. Oncotarget. 2015;6(29):28120-31.
25. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11(6):859-71.
26. Hwang Y, Kim LC, Song W, Edwards DN, Cook RS, Chen J. Disruption of the Scaffolding Function of mLST8 Selectively Inhibits mTORC2 Assembly and Function and Suppresses mTORC2-Dependent Tumor Growth In Vivo. Cancer Res. 2019;79(13):3178-3184.
27. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21-35.
28. Griffith JL, Wong M. The mTOR pathway in treatment of epilepsy: a clinical update. Future Neurol. 2018;13(2):49-58.
29. Angliker N, Rüegg MA. In vivo evidence for mTORC2-mediated actin cytoskeleton rearrangement in neurons. Bioarchitecture. 2013;3(4):113-8.
30. Dahl KD, Almeida AR, Hathaway HA, Bourne J, Brown TL, Finseth LT, Wood TL, Macklin WB. mTORC2 Loss in Oligodendrocyte Progenitor Cells Results in Regional Hypomyelination in the Central Nervous System. J Neurosci. 2023;43(4):540-558.
31. Thomanetz V, Angliker N, Cloëtta D, Lustenberger RM, Schweighauser M, Oliveri F, Suzuki N, Rüegg MA. Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J Cell Biol. 2013;201(2):293-308.
32. Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M, Krnjević K, Roman G, Costa-Mattioli M. mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci. 2013;16(4):441-8.
33. Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 2021;101(3):1371-1426.
34. McCabe MP, Cullen ER, Barrows CM, Shore AN, Tooke KI, Laprade KA, Stafford JM, Weston MC. Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission. Elife. 2020;9:e51440.
35. Kosillo P, Ahmed KM, Aisenberg EE, Karalis V, Roberts BM, Cragg SJ, Bateup HS. Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2. Elife. 2022;11:e75398.
36. Urbanska M, Gozdz A, Swiech LJ, Jaworski J. Mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) control the dendritic arbor morphology of hippocampal neurons. J Biol Chem. 2012;287(36):30240-56.
37. Cullen ER, Tariq K, Shore AN, Luikart BW, Weston MC. mTORC2 Inhibition Improves Morphological Effects of PTEN Loss, But Does Not Correct Synaptic Dysfunction or Prevent Seizures. J Neurosci. 2023;43(5):827-845.
38. Jansen LA, Mirzaa GM, Ishak GE, O'Roak BJ, Hiatt JB, Roden WH, Gunter SA, Christian SL, Collins S, Adams C, Rivière JB, St-Onge J, Ojemann JG, Shendure J, Hevner RF, Dobyns WB. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain. 2015;138(Pt 6):1613-28.
39. Lee HK, Kwon B, Lemere CA, de la Monte S, Itamura K, Ha AY, Querfurth HW. mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons. J Alzheimers Dis. 2017;56(3):1015-1036.
40. Swiech L, Perycz M, Malik A, Jaworski J. Role of mTOR in physiology and pathology of the nervous system. Biochim Biophys Acta. 2008; 1784(1):116-32.
1. Liu, M., Li, G., Song, X. et al. Prevalence, risk factors, and prognosis of central nervous system manifestations in antiphospholipid syndrome. Sci Rep 13, 8915 (2023).
2. Maiese K. The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk. Front Immunol. 2023 Nov 8;14:1273570.
3. Sanghai N, Tranmer GK. Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View. Cells. 2023;12(18):2318.
4. Kaur A, Sharma S. Mammalian target of rapamycin (mTOR) as a potential therapeutic target in various diseases. Inflammopharmacology. 2017;25(3):293-312.
5. Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014 Oct 22;84(2):275-91.
6. Rabanal-Ruiz Y, Otten EG, Korolchuk VI. mTORC1 as the main gateway to autophagy. Essays Biochem. 2017; 61(6):565-584.
7. Bockaert J, Marin P. mTOR in Brain Physiology and Pathologies. Physiol Rev. 2015;95(4):1157-87.
8. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93.
9. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307(5712):1098-101.
10. Fu W, Hall MN. Regulation of mTORC2 Signaling. Genes (Basel). 2020;11(9):1045.
11. Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall MN. Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proc Natl Acad Sci U S A. 2013;110(31):12526-34.
12. Ebner M, Sinkovics B, Szczygieł M, Ribeiro DW, Yudushkin I. Localization of mTORC2 activity inside cells. J Cell Biol. 2017 Feb;216(2):343-353. Ebner M, Sinkovics B, Szczygieł M, Ribeiro DW, Yudushkin I. Localization of mTORC2 activity inside cells. J Cell Biol. 2017;216(2):343-353.
13. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960-976.
14. Heras-Sandoval D, Pérez-Rojas JM, Pedraza-Chaverri J. Novel compounds for the modulation of mTOR and autophagy to treat neurodegenerative diseases. Cell Signal. 2020; 65:109442.
15. Jaworski J, Sheng M. The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol. 2006;34(3):205-19.
16. Kazyken D, Magnuson B, Bodur C, Acosta-Jaquez HA, Zhang D, Tong X et al. AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. Sci Signal. 2019; 12(585):eaav3249.
17. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296-302.
18. Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, Liu D, Wan L, Zhai B, Yu Y, Yuan M, Kim BM, Shaik S, Menon S, Gygi SP, Lee TH, Asara JM, Manning BD, Blenis J, Su B, Wei W. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol. 2013;15(11):1340-50.
19. Bové J, Martínez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci. 2011;12(8):437-52.
20. Yuan HX, Guan KL. The SIN1-PH Domain Connects mTORC2 to PI3K. Cancer Discov. 2015;5(11):1127-9.
21. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127(1):125-37.
22. Kocalis HE, Hagan SL, George L, Turney MK, Siuta MA, Laryea GN, Morris LC, Muglia LJ, Printz RL, Stanwood GD, Niswender KD. Rictor/mTORC2 facilitates central regulation of energy and glucose homeostasis. Mol Metab. 2014;3(4):394-407.
23. Treins C, Warne PH, Magnuson MA, Pende M, Downward J. Rictor is a novel target of p70 S6 kinase-1. Oncogene. 2010;29(7):1003-16.
24. Laugier F, Finet-Benyair A, André J, Rachakonda PS, Kumar R, Bensussan A, Dumaz N. RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma. Oncotarget. 2015;6(29):28120-31.
25. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11(6):859-71.
26. Hwang Y, Kim LC, Song W, Edwards DN, Cook RS, Chen J. Disruption of the Scaffolding Function of mLST8 Selectively Inhibits mTORC2 Assembly and Function and Suppresses mTORC2-Dependent Tumor Growth In Vivo. Cancer Res. 2019;79(13):3178-3184.
27. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21-35.
28. Griffith JL, Wong M. The mTOR pathway in treatment of epilepsy: a clinical update. Future Neurol. 2018;13(2):49-58.
29. Angliker N, Rüegg MA. In vivo evidence for mTORC2-mediated actin cytoskeleton rearrangement in neurons. Bioarchitecture. 2013;3(4):113-8.
30. Dahl KD, Almeida AR, Hathaway HA, Bourne J, Brown TL, Finseth LT, Wood TL, Macklin WB. mTORC2 Loss in Oligodendrocyte Progenitor Cells Results in Regional Hypomyelination in the Central Nervous System. J Neurosci. 2023;43(4):540-558.
31. Thomanetz V, Angliker N, Cloëtta D, Lustenberger RM, Schweighauser M, Oliveri F, Suzuki N, Rüegg MA. Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J Cell Biol. 2013;201(2):293-308.
32. Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M, Krnjević K, Roman G, Costa-Mattioli M. mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci. 2013;16(4):441-8.
33. Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 2021;101(3):1371-1426.
34. McCabe MP, Cullen ER, Barrows CM, Shore AN, Tooke KI, Laprade KA, Stafford JM, Weston MC. Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission. Elife. 2020;9:e51440.
35. Kosillo P, Ahmed KM, Aisenberg EE, Karalis V, Roberts BM, Cragg SJ, Bateup HS. Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2. Elife. 2022;11:e75398.
36. Urbanska M, Gozdz A, Swiech LJ, Jaworski J. Mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) control the dendritic arbor morphology of hippocampal neurons. J Biol Chem. 2012;287(36):30240-56.
37. Cullen ER, Tariq K, Shore AN, Luikart BW, Weston MC. mTORC2 Inhibition Improves Morphological Effects of PTEN Loss, But Does Not Correct Synaptic Dysfunction or Prevent Seizures. J Neurosci. 2023;43(5):827-845.
38. Jansen LA, Mirzaa GM, Ishak GE, O'Roak BJ, Hiatt JB, Roden WH, Gunter SA, Christian SL, Collins S, Adams C, Rivière JB, St-Onge J, Ojemann JG, Shendure J, Hevner RF, Dobyns WB. PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain. 2015;138(Pt 6):1613-28.
39. Lee HK, Kwon B, Lemere CA, de la Monte S, Itamura K, Ha AY, Querfurth HW. mTORC2 (Rictor) in Alzheimer's Disease and Reversal of Amyloid-β Expression-Induced Insulin Resistance and Toxicity in Rat Primary Cortical Neurons. J Alzheimers Dis. 2017;56(3):1015-1036.
40. Swiech L, Perycz M, Malik A, Jaworski J. Role of mTOR in physiology and pathology of the nervous system. Biochim Biophys Acta. 2008; 1784(1):116-32.
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2025/10/30
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