MTORC2

Last updated
mTOR
Identifiers
Symbol MTOR
Alt. symbolsFRAP, FRAP2, FRAP1
NCBI gene 2475
HGNC 3942
OMIM 601231
RefSeq NM_004958
UniProt P42345
Other data
EC number 2.7.11.1
Locus Chr. 1 p36
Search for
Structures Swiss-model
Domains InterPro
RICTOR
Identifiers
Symbol RICTOR
NCBI gene 253260
HGNC 28611
RefSeq NM_152756
Other data
Locus Chr. 5 p13.1
MLST8
Identifiers
Symbol MLST8
NCBI gene 64223
HGNC 24825
OMIM 612190
RefSeq NM_022372
UniProt Q9BVC4
Other data
Locus Chr. 16 p13.3
Search for
Structures Swiss-model
Domains InterPro
MAPKAP1
Identifiers
Symbol MAPKAP1
NCBI gene 79109
HGNC 18752
OMIM 610558
RefSeq NM_001006617.1
UniProt Q9BPZ7
Other data
Locus Chr. 9 q34.11
Search for
Structures Swiss-model
Domains InterPro

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]

Contents

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 and neutrophils, mTORC2 facilitates actin polymerization. [18] [19] [20] 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. [21] In contrast to TORC1, which is mainly stimulated by nutrients, TORC2 is mainly stimulated by growth factors. [22] 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. [23] 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. [24] [25] Torin-1 can also be used to inhibit mTORC2. [13] [26]

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] [27] [28]

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. [29] Additionally, some components of G protein signalling has been revealed as important regulators of mTORC2 activity as Ric-8B protein and some lipid metabolites. [30] [31] [32]

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 [33] but is able to phosphorylate other members of the PKC family that have various regulatory functions in cell migration and cytoskeletal remodeling. [34] [35] mTORC2 plays a pivotal role in phosphorylation and thus in activation of Akt, which is a vital signaling component downstream from PI3K once active, [36] and also in phosphorylation of SGK1, PKC [37] and HDACs. [38] [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. [39] In many types of human cancer, hyperactivation of mTORC2 caused by mutations and aberrant amplifications of mTORC2 core components is frequently observed. [40] On metabolic level, activation of mTORC2 stimulates processes related to alteration of glucose metabolism in cancer cells, altogether known as Warburg effect. [41] mTORC2-mediated lipogenesis has been linked to promotion of hepatocellular carcinoma through stimulation of glycerophospholipid and sphingolipid synthesis. [42]

Although mTORC2 is acutely insensitive to rapamycin, chronic rapamycin treatment abrogates mTORC2 signaling, leading to insulin resistance and glucose intolerance. [1] [43] [12] By contrast, dietary administration of Torin1, a dual mTORC1/2 inhibitor, resulted in prolonged lifespan in D. melanogaster with no reduction in fertility [44] and Akt haploinsufficiency, an mTORC2 downstream target, extended lifespan in mice. [45]

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. [46]

Chronic mTORC2 activity may play a role in systemic lupus erythematosus by impairing lysosome function. [47]

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. [48] [49] [50] [51] [52] Adipose-specific disruption of mTORC2 through deletion of Rictor may protect from a high-fat diet in young mice, [53] but results in hepatic steatosis and insulin resistance in older mice. [54] 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. [55] [56] [57] Loss of mTORC2/Rictor in pancreatic beta cells results in reduced beta cell mass and insulin secretion, and hyperglycemia and glucose intolerance. [58] 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. [59]

Related Research Articles

<span class="mw-page-title-main">Protein kinase B</span> Set of three serine threonine-specific protein kinases

Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

mTOR Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

<span class="mw-page-title-main">Branched-chain amino acid</span> Amino acid with a branched carbon chain

A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch. Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and valine. Non-proteinogenic BCAAs include 2-aminoisobutyric acid and alloisoleucine.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

Nesfatin-1 is a neuropeptide produced in the hypothalamus of mammals. It participates in the regulation of hunger and fat storage. Increased nesfatin-1 in the hypothalamus contributes to diminished hunger, a 'sense of fullness', and a potential loss of body fat and weight.

<span class="mw-page-title-main">Folliculin</span> Protein-coding gene

The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.

<span class="mw-page-title-main">TSC2</span> Mammalian protein found in Homo sapiens

Tuberous sclerosis complex 2 (TSC2), also known as tuberin, is a protein that in humans is encoded by the TSC2 gene.

<span class="mw-page-title-main">RHEB</span> Protein-coding gene in the species Homo sapiens

RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle.

<span class="mw-page-title-main">P70-S6 Kinase 1</span> Protein-coding gene in the species Homo sapiens

Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase, is an enzyme that in humans is encoded by the RPS6KB1 gene. It is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway. As the name suggests, its target substrate is the S6 ribosomal protein. Phosphorylation of S6 induces protein synthesis at the ribosome.

<span class="mw-page-title-main">RPTOR</span> Protein-coding gene in humans

Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.

<span class="mw-page-title-main">MAPKAP1</span> Protein-coding gene in the species Homo sapiens

Target of rapamycin complex 2 subunit MAPKAP1 is a protein that in humans is encoded by the MAPKAP1 gene. As the name indicates, it is a subunit of mTOR complex 2.

<span class="mw-page-title-main">RICTOR</span> Protein-coding gene in the species Homo sapiens

Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the RICTOR gene.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

AuTophaGy related 1 (Atg1) is a 101.7kDa serine/threonine kinase in S.cerevisiae, encoded by the gene ATG1. It is essential for the initial building of the autophagosome and Cvt vesicles. In a non-kinase role it is - through complex formation with Atg13 and Atg17 - directly controlled by the TOR kinase, a sensor for nutrient availability.

<span class="mw-page-title-main">MLST8</span> Protein-coding gene in humans

Target of rapamycin complex subunit LST8, also known as mammalian lethal with SEC13 protein 8 (mLST8) or TORC subunit LST8 or G protein beta subunit-like, is a protein that in humans is encoded by the MLST8 gene. It is a subunit of both mTORC1 and mTORC2, complexes that regulate cell growth and survival in response to nutrient, energy, redox, and hormonal signals. It is upregulated in several human colon and prostate cancer cell lines and tissues. Knockdown of mLST8 prevented mTORC formation and inhibited tumor growth and invasiveness.

mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs used to treat several human diseases, including cancer, autoimmune diseases, and neurodegeneration. They function by inhibiting the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

mTORC1 Protein complex

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.

<span class="mw-page-title-main">Michael N. Hall</span> American-Swiss molecular biologist

Michael Nip Hall is an American-Swiss molecular biologist and professor at the Biozentrum of the University of Basel, Switzerland. He discovered TOR, a protein central for regulating cell growth.

Immunometabolism is a branch of biology that studies the interplay between metabolism and immunology in all organisms. In particular, immunometabolism is the study of the molecular and biochemical underpinninngs for i) the metabolic regulation of immune function, and ii) the regulation of metabolism by molecules and cells of the immune system. Further categorization includes i) systemic immunometabolism and ii) cellular immunometabolism. Immunometabolism includes metabolic inflammation:a chronic, systemic, low grade inflammation, orchestrated by metabolic deregulation caused by obesity or aging.

<span class="mw-page-title-main">Torin-1</span> Chemical compound

Torin-1 is a drug which was one of the first non-rapalog derived inhibitors of the mechanistic target of rapamycin (mTOR) subtypes mTORC1 and mTORC2. In animal studies it has anti-inflammatory, anti-cancer, and anti-aging properties, and shows activity against neuropathic pain.

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. Bibcode:2004CBio...14.1296D. doi: 10.1016/j.cub.2004.06.054 . PMID   15268862. S2CID   4658268.
  8. 1 2 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. Bibcode:2005Sci...307.1098S. doi:10.1126/science.1106148. PMID   15718470. S2CID   45837814.
  9. ↑ Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, et al. (January 1998). "Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B". Science. 279 (5351): 710–4. Bibcode:1998Sci...279..710S. doi:10.1126/science.279.5351.710. PMID   9445477.
  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.
  15. ↑ Yin Y, Hua H, Li M, Liu S, Kong Q, Shao T, et al. (January 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.
  16. ↑ Zoncu R, Efeyan A, Sabatini DM (January 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.
  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.
  18. 1 2 Costa-Mattioli M, Monteggia LM (2013). "mTOR complexes in neurodevelopmental and neuropsychiatric disorders". Nature Neuroscience . 16 (11): 1537–1543. doi:10.1038/nn.3546. PMID   24165680. S2CID   7820105.
  19. ↑ Pal, Dhiman Sankar; Banerjee, Tatsat; Lin, Yiyan; de Trogoff, Félix; Borleis, Jane; Iglesias, Pablo A.; Devreotes, Peter N. (July 2023). "Actuation of single downstream nodes in growth factor network steers immune cell migration". Developmental Cell. 58 (13): 1170–1188.e7. doi:10.1016/j.devcel.2023.04.019. ISSN   1534-5807. PMC   10524337 . PMID   37220748.
  20. ↑ Lin, Yiyan; Pal, Dhiman Sankar; Banerjee, Parijat; Banerjee, Tatsat; Qin, Guanghui; Deng, Yu; Borleis, Jane; Iglesias, Pablo A.; Devreotes, Peter N. (2024-07-01). "Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration". Nature Cell Biology. 26 (7): 1062–1076. doi:10.1038/s41556-024-01453-4. ISSN   1476-4679. PMC  11364469. PMID   38951708.
  21. ↑ Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM (September 2006). "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s". Current Biology. 16 (18): 1865–70. Bibcode:2006CBio...16.1865F. doi: 10.1016/j.cub.2006.08.001 . PMID   16919458. S2CID   8239162.
  22. ↑ Bockaert J, Marin P (2015). "mTOR in Brain Physiology and Pathologies". Physiological Reviews . 95 (4): 1157–1187. doi:10.1152/physrev.00038.2014. PMID   26269525.
  23. ↑ Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. (April 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.
  24. ↑ Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, et al. (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.
  25. ↑ Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. (March 2012). "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity". Science. 335 (6076): 1638–43. Bibcode:2012Sci...335.1638L. doi:10.1126/science.1215135. PMC   3324089 . PMID   22461615.
  26. ↑ Liu Q, Chang JW, Wang J, Kang SA, Thoreen CC, Markhard A, et al. (October 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.
  27. ↑ Liu P, Gan W, Chin YR, Ogura K, Guo J, Zhang J, et al. (November 2015). "PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex". Cancer Discovery. 5 (11): 1194–209. doi:10.1158/2159-8290.CD-15-0460. PMC   4631654 . PMID   26293922.
  28. ↑ Yang G, Murashige DS, Humphrey SJ, James DE (August 2015). "A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation". Cell Reports. 12 (6): 937–43. doi: 10.1016/j.celrep.2015.07.016 . hdl: 11858/00-001M-0000-0028-463C-B . PMID   26235620.
  29. ↑ Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, et al. (June 2011). "The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling". Science. 332 (6035): 1317–22. Bibcode:2011Sci...332.1317H. doi:10.1126/science.1199498. PMC   3177140 . PMID   21659604.
  30. ↑ Nagai MH, Xavier VP, Gutiyama LM, Machado CF, Reis AH, Donnard ER, et al. (May 2020). "Depletion of Ric-8B leads to reduced mTORC2 activity". PLOS Genetics. 16 (5): e1008255. doi: 10.1371/journal.pgen.1008255 . PMC   7252638 . PMID   32392211.
  31. ↑ Mullins GR, Wang L, Raje V, Sherwood SG, Grande RC, Boroda S, et al. (December 2014). "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. Bibcode:2014PNAS..11117450M. doi: 10.1073/pnas.1410530111 . PMC   4267365 . PMID   25422441.
  32. ↑ Zhang C, Wendel AA, Keogh MR, Harris TE, Chen J, Coleman RA (January 2012). "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. Bibcode:2012PNAS..109.1667Z. doi: 10.1073/pnas.1110730109 . PMC   3277174 . PMID   22307628.
  33. ↑ Chen J, Holguin N, Shi Y, Silva MJ, Long F (February 2015). "mTORC2 signaling promotes skeletal growth and bone formation in mice". Journal of Bone and Mineral Research. 30 (2): 369–78. doi:10.1002/jbmr.2348. PMC   4322759 . PMID   25196701.
  34. ↑ Cameron AJ, Linch MD, Saurin AT, Escribano C, Parker PJ (October 2011). "mTORC2 targets AGC kinases through Sin1-dependent recruitment" (PDF). The Biochemical Journal. 439 (2): 287–97. doi:10.1042/BJ20110678. PMID   21806543.
  35. ↑ 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.
  36. ↑ Jhanwar-Uniyal M, Amin AG, Cooper JB, Das K, Schmidt MH, Murali R (May 2017). "Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects". Advances in Biological Regulation. 64: 39–48. doi:10.1016/j.jbior.2016.12.001. PMID   28189457.
  37. ↑ Linke M, Fritsch SD, Sukhbaatar N, Hengstschläger M, Weichhart T (October 2017). "mTORC1 and mTORC2 as regulators of cell metabolism in immunity". FEBS Letters. 591 (19): 3089–3103. doi:10.1002/1873-3468.12711. PMC   6322652 . PMID   28600802.
  38. ↑ Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T, et al. (November 2013). "mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc". Cell Metabolism. 18 (5): 726–39. doi:10.1016/j.cmet.2013.09.013. PMC   3840163 . PMID   24140020.
  39. ↑ Luo Y, Xu W, Li G, Cui W (2018-10-30). "Weighing In on mTOR Complex 2 Signaling: The Expanding Role in Cell Metabolism". Oxidative Medicine and Cellular Longevity. 2018: 7838647. doi: 10.1155/2018/7838647 . PMC   6232796 . PMID   30510625.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ Guri Y, Colombi M, Dazert E, Hindupur SK, Roszik J, Moes S, et al. (December 2017). "mTORC2 Promotes Tumorigenesis via Lipid Synthesis". Cancer Cell. 32 (6): 807–823.e12. doi: 10.1016/j.ccell.2017.11.011 . PMID   29232555.
  43. ↑ Maiese K (June 2020). "New Insights for nicotinamide: Metabolic disease, autophagy, and mTOR". Frontiers in Bioscience. 25 (11): 1925–1973. doi:10.2741/4886. PMC   7265993 . PMID   32472766.
  44. ↑ 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.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ 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.
  48. ↑ 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.
  49. ↑ 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.
  50. ↑ 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.
  51. ↑ 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.
  52. ↑ 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.
  53. ↑ Cybulski N, Polak P, Auwerx J, Rüegg MA, Hall MN (June 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. Bibcode:2009PNAS..106.9902C. doi: 10.1073/pnas.0811321106 . PMC   2700987 . PMID   19497867.
  54. ↑ Kumar A, Lawrence JC, Jung DY, Ko HJ, Keller SR, Kim JK, et al. (June 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.
  55. ↑ 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.
  56. ↑ Kleinert M, Sylow L, Fazakerley DJ, Krycer JR, Thomas KC, Oxbøll AJ, et al. (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.
  57. ↑ 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.
  58. ↑ 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.
  59. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.