TORC2 Structure and Function

Trends in Biochemical Sciences

Volumn 41, Issue 6, 2016, Pages 532-545

  Gaubitz, Christl ^a   Prouteau, Manoel ^a   Kusmider, Beata ^a   Loewith, Robbie ^a  

^a UNIVERSITY OF GENEVA   (Switzerland)

Author keywords

Cancer; Conditional knockout mouse model; Cryo electron microscopy; Membrane tension homeostasis; Metabolism; Subunit conservation; Subunit topology; Target of rapamycin complex 2 (TORC2); Therapeutic potential

Indexed keywords

AVO1 PROTEIN; AVO2 PROTEIN; AVO3 PROTEIN; BIT61 PROTEIN; DEPTOR PROTEIN; GUANINE NUCLEOTIDE EXCHANGE FACTOR; GUANOSINE TRIPHOSPHATASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PRR5 PROTEIN; RAC1 PROTEIN; RYH1 PROTEIN; TARGET OF RAPAMYCIN KINASE; TORC1 PROTEIN; TORC2 PROTEIN; UNCLASSIFIED DRUG; ANTINEOPLASTIC ANTIBIOTIC; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MULTIPROTEIN COMPLEX; PROTEIN BINDING; PROTEIN SUBUNIT; RAPAMYCIN; TOR COMPLEX 2;

CELL MEMBRANE; GENE DELETION; NONHUMAN; PRIORITY JOURNAL; PROTEIN ACETYLATION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN SUBUNIT; REVIEW; STRUCTURE ACTIVITY RELATION; TRANSCRIPTION REGULATION; ALPHA HELIX; ANIMAL; ANTAGONISTS AND INHIBITORS; BINDING SITE; CHEMISTRY; GENE EXPRESSION REGULATION; GENETICS; HUMAN; KNOCKOUT MOUSE; METABOLISM; MOLECULAR MODEL; MOUSE; PROTEIN DOMAIN; SIGNAL TRANSDUCTION;

ANIMALS; ANTIBIOTICS, ANTINEOPLASTIC; BINDING SITES; GENE EXPRESSION REGULATION; HUMANS; MICE; MICE, KNOCKOUT; MODELS, MOLECULAR; MULTIPROTEIN COMPLEXES; PROTEIN BINDING; PROTEIN CONFORMATION, ALPHA-HELICAL; PROTEIN INTERACTION DOMAINS AND MOTIFS; PROTEIN SUBUNITS; SIGNAL TRANSDUCTION; SIROLIMUS; STRUCTURE-ACTIVITY RELATIONSHIP; TOR SERINE-THREONINE KINASES;

EID: 84964997376     PISSN: 09680004     EISSN: 13624326     Source Type: Journal    
DOI: 10.1016/j.tibs.2016.04.001     Document Type: Review

References (122)

1. Sehgal S.N., et al. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J. Antibiot. (Tokyo) 1975, 28:727-732.
2. Vezina C., et al. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. (Tokyo) 1975, 28:721-726.
3. Benjamin D., et al. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat. Rev. Drug Discov. 2011, 10:868-880.
4. Houchens D.P., et al. Human brain tumor xenografts in nude mice as a chemotherapy model. Eur. J. Cancer Clin. Oncol. 1983, 19:799-805.
5. Heitman J., et al. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991, 253:905-909.
6. Loewith R., et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 2002, 10:457-468.
7. Wedaman K.P., et al. Tor kinases are in distinct membrane-associated protein complexes in Saccharomyces cerevisiae. Mol. Biol. Cell 2003, 14:1204-1220.
8. Hara K., et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002, 110:177-189.
9. Jacinto E., et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 2004, 6:1122-1128.
10. Kim D-H., et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002, 110:163-175.
11. Sarbassov D.D., et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 2004, 14:1296-1302.
12. van Dam T.J.P., et al. Evolution of the TOR Pathway. J. Mol. Evol. 2011, 73:209-220.
13. Loewith R., Hall M.N. Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 2011, 189:1177-1201.
14. Panchaud N., et al. SEACing the GAP that nEGOCiates TORC1 activation: evolutionary conservation of Rag GTPase regulation. Cell Cycle 2013, 12:2948-2952.
15. Zoncu R., et al. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 2011, 12:21-35.
16. Gaubitz C., et al. Molecular basis of the rapamycin insensitivity of target of rapamycin complex 2. Mol. Cell 2015, 58:977-988.
17. Kliegman J.I., et al. Chemical genetics of rapamycin-insensitive TORC2 in S. cerevisiae. Cell Rep. 2013, 5:1725-1736.
18. Rispal D., et al. Target of rapamycin complex 2 regulates actin polarization and endocytosis via multiple pathways. J. Biol. Chem. 2015, 290:14963-14978.
19. Rexin D., et al. TOR signalling in plants. Biochem. J. 2015, 470:1-14.
20. Yip C.K., et al. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell 2010, 38:768-774.
21. Aylett C.H.S., et al. Architecture of human mTOR complex 1. Science 2016, 351:48-52.
22. Yang H., et al. mTOR kinase structure, mechanism and regulation. Nature 2013, 497:217-223.
23. Baretić D., et al. Tor forms a dimer through an N-terminal helical solenoid with a complex topology. Nat. Commun. 2016, Published online April 13, 2016. 10.1038/ncomms11016.
24. Keith C.T., Schreiber S.L. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 1995, 270:50-51.
25. Neer E.J., et al. The ancient regulatory-protein family of WD-repeat proteins. Nature 1994, 371:297-300.
26. Wullschleger S., et al. Molecular organization of target of rapamycin complex 2. J. Biol. Chem. 2005, 280:30697-30704.
27. Javadi Y., Itzhaki L.S. Tandem-repeat proteins: regularity plus modularity equals design-ability. Curr. Opin. Struct. Biol. 2013, 23:622-631.
28. Marchler-Bauer A. CDD: a Conserved Domain Database for protein classification. Nucleic Acids Res. 2004, 33:D192-D196.
29. Lee S., et al. A novel Ras-interacting protein required for chemotaxis and cyclic adenosine monophosphate signal relay in Dictyostelium. Mol. Biol. Cell 1999, 10:2829-2845.
30. Colicelli J., et al. Expression of three mammalian cDNAs that interfere with RAS function in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. U.S.A. 1991, 88:2913-2917.
31. Lee S., et al. TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol. Biol. Cell 2005, 16:4572-4583.
32. Schroder W.A., et al. Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling. Cell. Signal. 2007, 19:1279-1289.
33. Berchtold D., Walther T.C. TORC2 plasma membrane localization is essential for cell viability and restricted to a distinct domain. Mol. Biol. Cell 2009, 20:1565-1575.
34. Gallego O., et al. A systematic screen for protein-lipid interactions in Saccharomyces cerevisiae. Mol. Syst. Biol. 2010, 6:430.
35. Pan D., Matsuura Y. Structures of the pleckstrin homology domain of Saccharomyces cerevisiae Avo1 and its human orthologue Sin1, an essential subunit of TOR complex 2. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 2012, 68:386-392.
36. Schroder W., et al. Alternative polyadenylation and splicing of mRNAs transcribed from the human Sin1 gene. Gene 2004, 339:17-23.
37. Cameron A.J.M., et al. mTORC2 targets AGC kinases through Sin1-dependent recruitment. Biochem. J. 2011, 439:287-297.
38. Liao H-C., Chen M-Y. Target of rapamycin complex 2 signals to downstream effector yeast protein kinase 2 (Ypk2) through adheres-voraciously-to-target-of-rapamycin-2 protein 1 (Avo1) in Saccharomyces cerevisiae. J. Biol. Chem. 2012, 287:6089-6099.
39. Polak P., Hall M.N. mTORC2 caught in a SINful Akt. Dev. Cell 2006, 11:433-434.
40. Frias M.A., et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 2006, 16:1865-1870.
41. Yuan Y., et al. Characterization of Sin1 isoforms reveals an mTOR-dependent and independent function of Sin1γ. PLoS ONE 2015, 10:e0135017.
42. Pearce L.R., et al. Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem. J. 2011, 436:169-179.
43. Thedieck K., et al. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS ONE 2007, 2:e1217.
44. Woo S-Y., et al. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J. Biol. Chem. 2007, 282:25604-25612.
45. Gatherar I., et al. Identification of a novel gene hbrB required for polarised growth in Aspergillus nidulans. Fungal Genet. Biol. 2004, 41:463-471.
46. Goujon M., et al. A new bioinformatics analysis tools framework at EMBL-EBI. Nucleic Acids Res. 2010, 38:W695-W699.
47. Fadri M., et al. The pleckstrin homology domain proteins Slm1 and Slm2 are required for actin cytoskeleton organization in yeast and bind phosphatidylinositol-4,5-bisphosphate and TORC2. Mol. Biol. Cell 2005, 16:1883-1900.
48. Peterson T.R., et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009, 137:873-886.
49. Consonni S.V., et al. DEP domains: structurally similar but functionally different. Nat. Rev. Mol. Cell Biol. 2014, 15:357-362.
50. Berchtold D., et al. Plasma membrane stress induces relocalization of Slm proteins and activation of TORC2 to promote sphingolipid synthesis. Nat. Cell Biol. 2012, 14:542-547.
51. Douglas L.M., Konopka J.B. Fungal membrane organization: the eisosome concept. Annu. Rev. Microbiol. 2014, 68:377-393.
52. Kabeche R., et al. Eisosomes provide membrane reservoirs for rapid expansion of the yeast plasma membrane. J. Cell Sci. 2015, 128:4057-4062.
53. Niles B.J., et al. Plasma membrane recruitment and activation of the AGC kinase Ypk1 is mediated by target of rapamycin complex 2 (TORC2) and its effector proteins Slm1 and Slm2. Proc. Natl. Acad. Sci. U.S.A. 2012, 109:1536-1541.
54. Kippenberger S., et al. Mechanical stretch stimulates protein kinase B/Akt phosphorylation in epidermal cells via angiotensin II type 1 receptor and epidermal growth factor receptor. J. Biol. Chem. 2005, 280:3060-3067.
55. Sedding D.G. Caveolin-1 facilitates mechanosensitive protein kinase B (Akt) signaling in vitro and in vivo. Circ. Res. 2005, 96:635-642.
56. Yu J. Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels. J. Clin. Invest. 2006, 116:1284-1291.
57. Zhang B., et al. Caveolin-1 phosphorylation is required for stretch-induced EGFR and Akt activation in mesangial cells. Cell. Signal. 2007, 19:1690-1700.
58. Chen C-H., et al. ER stress inhibits mTORC2 and Akt signaling through GSK-3β-mediated phosphorylation of rictor. Sci. Signal 2011, 4. ra10.
59. Muir A., et al. TORC2-dependent protein kinase Ypk1 phosphorylates ceramide synthase to stimulate synthesis of complex sphingolipids. Elife 2014, 3:e03779.
60. Betz C., Hall M.N. Where is mTOR and what is it doing there?. J. Cell Biol. 2013, 203:563-574.
61. Arias E., et al. Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy. Mol. Cell 2015, 59:270-284.
62. Gan X., et al. Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 2011, 286:10998-11002.
63. Liu P., et al. PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov 2015, 5:1194-1209.
64. Swaney D.L., et al. Global analysis of phosphorylation and ubiquitylation cross-talk in protein degradation. Nat. Methods 2013, 10:676-682.
65. Dibble C.C., et al. Characterization of rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol. Cell. Biol. 2009, 29:5657-5670.
66. Glidden E.J., et al. Multiple site acetylation of Rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of Akt protein. J. Biol. Chem. 2012, 287:581-588.
67. Masui K., et al. mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab. 2013, 18:726-739.
68. Choudhary C., et al. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol. 2014, 15:536-550.
69. Nomura W., Inoue Y. Methylglyoxal activates the target of rapamycin complex 2-protein kinase C signaling pathway in Saccharomyces cerevisiae. Mol. Cell. Biol. 2015, 35:1269-1280.
70. Hatano T., et al. Fission yeast Ryh1 GTPase activates TOR complex 2 in response to glucose. Cell Cycle 2015, 14:848-856.
71. Tatebe H., et al. Rab-family GTPase regulates TOR complex 2 signaling in fission yeast. Curr. Biol. 2010, 20:1975-1982.
72. Saci A., et al. Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol. Cell 2011, 42:50-61.
73. Cai W., Andres D.A. mTORC2 is required for Rit-mediated oxidative stress resistance. PLoS ONE 2014, 9:e115602.
74. Niles B.J., Powers T. TOR complex 2-Ypk1 signaling regulates actin polarization via reactive oxygen species. Mol. Biol. Cell 2014, 25:3962-3972.
75. Khanna N., et al. XPLN is an endogenous inhibitor of mTORC2. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:15979-15984.
76. Oh W.J., et al. mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J. 2010, 29:3939-3951.
77. Zinzalla V., et al. Activation of mTORC2 by association with the ribosome. Cell 2011, 144:757-768.
78. Pearce L.R., et al. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 2010, 11:9-22.
79. Kamada Y., et al. Tor2 directly phosphorylates the AGC kinase Ypk2 to regulate actin polarization. Mol. Cell. Biol. 2005, 25:7239-7248.
80. Roelants F.M. Differential roles of PDK1- and PDK2-phosphorylation sites in the yeast AGC kinases Ypk1, Pkc1 and Sch9. Microbiology 2004, 150:3289-3304.
81. Eltschinger S., Loewith R. TOR complexes and the maintenance of cellular homeostasis. Trends Cell Biol 2016, 26:148-159.
82. Shimada K., et al. TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks. Mol. Cell 2013, 51:829-839.
83. García-Martínez J.M., Alessi D.R. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 2008, 416:375-385.
84. Guertin D.A., et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell 2006, 11:859-871.
85. Ikenoue T., et al. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 2008, 27:1919-1931.
86. Sarbassov D.D., et al. Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science 2005, 307:1098-1101.
87. Sparks C.A., Guertin D.A. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 2010, 29:3733-3744.
88. Kumar A., et al. Muscle-specific deletion of Rictor impairs insulin-stimulated glucose transport and enhances basal glycogen synthase activity. Mol. Cell. Biol. 2008, 28:61-70.
89. Bentzinger C.F., et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 2008, 8:411-424.
90. Bozulic L., Hemmings B.A. PIKKing on PKB: regulation of PKB activity by phosphorylation. Cell Regul. 2009, 21:256-261.
91. Hung C-M., et al. Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep. 2014, 8:256-271.
92. Shiota C., et al. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev. Cell 2006, 11:583-589.
93. Aimi F., et al. Endothelial Rictor is crucial for midgestational development and sustained and extensive FGF2-induced neovascularization in the adult. Sci. Rep. 2015, 5:17705.
94. Wang S., et al. Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways. Mol. Cell. Biol. 2015, 35:1299-1313.
95. Thomanetz V., et al. Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J. Cell Biol. 2013, 201:293-308.
96. Chou P-C., et al. Mammalian target of rapamycin complex 2 modulates TCR processing and surface expression during thymocyte development. J. Immunol. 2014, 193:1162-1170.
97. Lee K., et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 2010, 32:743-753.
98. Cybulski N., et al. mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:9902-9907.
99. Kumar A., et al. Fat cell-specific ablation of Rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 2010, 59:1397-1406.
100. Gu Y., et al. Rictor/mTORC2 is essential for maintaining a balance between β-cell proliferation and cell size. Diabetes 2011, 60:827-837.
101. Hagiwara A., et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 2012, 15:725-738.
102. Lamming D.W., et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012, 335:1638-1643.
103. Lamming D.W., et al. Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2). FASEB J. 2014, 28:300-315.
104. Arriola Apelo S.I., et al. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 2016, 15:28-38.
105. Lamming D.W., et al. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 2013, 123:980-989.
106. Sciarretta S., et al. mTORC2 regulates cardiac response to stress by inhibiting MST1. Cell Rep. 2015, 11:125-136.
107. Lamming D.W., et al. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 2014, 13:911-917.
108. Hietakangas V., Cohen S.M. Re-evaluating AKT regulation: role of TOR complex 2 in tissue growth. Genes Dev. 2007, 21:632-637.
109. Guertin D.A., et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 2009, 15:148-159.
110. Ciriello G., et al. Emerging landscape of oncogenic signatures across human cancers. Nat. Genet. 2013, 45:1127-1133.
111. Cheng H., et al. RICTOR amplification defines a novel subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors. Cancer Discov. 2015, 5:1262-1270.
112. Dan H.C., et al. Akt-dependent activation of mTORC1 complex involves phosphorylation of mTOR (mammalian target of rapamycin) by IB kinase (IKK). J. Biol. Chem. 2014, 289:25227-25240.
113. Ekim B., et al. mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression. Mol. Cell. Biol. 2011, 31:2787-2801.
114. Halova L., et al. Phosphorylation of the TOR ATP binding domain by AGC kinase constitutes a novel mode of TOR inhibition. J. Cell Biol. 2013, 203:595-604.
115. Holz M.K. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem. 2005, 280:26089-26093.
116. Copp J., et al. TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res. 2009, 69:1821-1827.
117. Julien L-A., et al. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol. Cell. Biol. 2010, 30:908-921.
118. Treins C., et al. Rictor is a novel target of p70 S6 kinase-1. Oncogene 2010, 29:1003-1016.
119. Humphrey S.J., et al. Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab. 2013, 17:1009-1020.
120. Liu P., et al. Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity. Protein Cell 2014, 5:171-177.
121. Yang G., et al. A positive feedback loop between Akt and mTORC2 via SIN1 phosphorylation. Cell Rep. 2015, 12:937-943.
122. Chen C-H., et al. Autoregulation of the mechanistic target of rapamycin (mTOR) complex 2 integrity is controlled by an ATP-dependent mechanism. J. Biol. Chem. 2013, 288:27019-27030.