1932

Abstract

Every eukaryotic cell contains two distinct multisubunit protein kinase complexes that each contain a TOR (target of rapamycin) protein as the catalytic subunit. These ensembles, designated TORC1 and TORC2, serve as nutrient and stress sensors, signal integrators, and regulators of cell growth and homeostasis, but they differ in their composition, localization, and function. TORC1, activated on the cytosolic surface of the vacuole (or, in mammalian cells, on the cytosolic surface of the lysosome), promotes biosynthesis and suppresses autophagy. TORC2, located primarily at the plasma membrane (PM), maintains the proper levels and bilayer distribution of all PM components (sphingolipids, glycerophospholipids, sterols, and integral membrane proteins), which are needed for the membrane expansion that accompanies cell growth and division and for combating insults to PM integrity. This review summarizes our current understanding of the assembly, structural features, subcellular distribution, and function and regulation of TORC2, obtained largely through studies conducted with .

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cellbio-011723-030346
2023-10-16
2024-06-24
Loading full text...

Full text loading...

/deliver/fulltext/cellbio/39/1/annurev-cellbio-011723-030346.html?itemId=/content/journals/10.1146/annurev-cellbio-011723-030346&mimeType=html&fmt=ahah

Literature Cited

  1. Albuquerque CP, Smolka MB, Payne SH, Bafna V, Eng J, Zhou H. 2008. A multidimensional chromatography technology for in-depth phosphoproteome analysis. Mol. Cell. Proteom. 7:1389–96
    [Google Scholar]
  2. Alcaide-Gavilán M, Lucena R, Banuelos S, Kellogg DR. 2020. Conserved Ark1-related kinases function in a TORC2 signaling network. Mol. Biol. Cell 31:2057–69
    [Google Scholar]
  3. Allan RK, Ratajczak T. 2011. Versatile TPR domains accommodate different modes of target protein recognition and function. Cell Stress Chaperones 16:353–67
    [Google Scholar]
  4. An P, Xu W, Luo J, Luo Y. 2021. Expanding TOR complex 2 signaling: emerging regulators and new connections. Front. Cell Dev. Biol. 9:713806
    [Google Scholar]
  5. Anand K, Maeda K, Gavin AC. 2012. Structural analyses of the Slm1-PH domain demonstrate ligand binding in the non-canonical site. PLOS ONE 7:e36526
    [Google Scholar]
  6. Aronova S, Wedaman K, Aronov PA, Fontes K, Ramos K et al. 2008. Regulation of ceramide biosynthesis by TOR complex 2. Cell Metab. 7:148–58
    [Google Scholar]
  7. Audhya A, Loewith R, Parsons AB, Gao L, Tabuchi M et al. 2004. Genome-wide lethality screen identifies new PI4,5P2 effectors that regulate the actin cytoskeleton. EMBO J. 23:3747–57
    [Google Scholar]
  8. Aylett CH, Sauer E, Imseng S, Boehringer D, Hall MN et al. 2016. Architecture of human mTOR complex 1. Science 351:48–52
    [Google Scholar]
  9. Ballon DR, Flanary PL, Gladue DP, Konopka JB, Dohlman HG, Thorner J. 2006. DEP-domain-mediated regulation of GPCR signaling responses. Cell 126:1079–93
    [Google Scholar]
  10. Baretić D, Berndt A, Ohashi Y, Johnson CM, Williams RL. 2016. Tor forms a dimer through an N-terminal helical solenoid with a complex topology. Nat. Commun. 7:11016
    [Google Scholar]
  11. Battaglioni S, Benjamin D, Wälchli M, Maier T, Hall MN. 2022. mTOR substrate phosphorylation in growth control. Cell 185:1814–36
    [Google Scholar]
  12. Beeler T, Bacikova D, Gable K, Hopkins L, Johnson C et al. 1998. The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2Δ mutant. J. Biol. Chem. 273:30688–94
    [Google Scholar]
  13. Berchtold D, Piccolis M, Chiaruttini N, Riezman I, Riezman H et al. 2012. Plasma membrane stress induces relocalization of Slm proteins and activation of TORC2 to promote sphingolipid synthesis. Nat. Cell Biol. 14:542–47
    [Google Scholar]
  14. Berchtold D, Walther TC. 2009. TORC2 plasma membrane localization is essential for cell viability and restricted to a distinct domain. Mol. Biol. Cell 20:1565–75
    [Google Scholar]
  15. Betz C, Hall MN. 2013. Where is mTOR and what is it doing there?. J. Cell Biol. 203:563–74
    [Google Scholar]
  16. Blandino-Rosano M, Scheys JO, Werneck-de-Castro JP, Louzada RA, Almaça J et al. 2022. Novel roles of mTORC2 in regulation of insulin secretion by actin filament remodeling. Am. J. Physiol. Endocrinol. Metab. 323:E133–44
    [Google Scholar]
  17. Broach JR. 2012. Nutritional control of growth and development in yeast. Genetics 192:73–105
    [Google Scholar]
  18. Brown EJ, Albers MW, Shin TB, Ichikaw K, Keith CT et al. 1994. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756–58
    [Google Scholar]
  19. Brunn GJ, Hudson CC, Sekulić A, Williams JM, Hosoi H et al. 1997. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277:99–101
    [Google Scholar]
  20. Bultynck G, Heath VL, Majeed AP, Galan JM, Haguenauer-Tsapis R, Cyert MS. 2006. Slm1 and Slm2 are novel substrates of the calcineurin phosphatase required for heat stress-induced endocytosis of the yeast uracil permease. Mol. Cell. Biol. 26:4729–45
    [Google Scholar]
  21. Cafferkey R, McLaughlin MM, Young PR, Johnson RK, Livi GP. 1994. Yeast TOR (DRR) proteins: amino-acid sequence alignment and identification of structural motifs. Gene 141:133–36
    [Google Scholar]
  22. Cafferkey R, Young P, McLaughlin MM, Bergsma DJ, Koltin Y et al. 1993. Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol. Cell. Biol. 13:6012–23
    [Google Scholar]
  23. Cameron AJ, Linch MD, Saurin AT, Escribano C, Parker PJ. 2011. mTORC2 targets AGC kinases through Sin1-dependent recruitment. Biochem. J. 439:287–97
    [Google Scholar]
  24. Carney DS, Davies BA, Horazdovsky BF. 2006. Vps9 domain-containing proteins: activators of Rab5 GTPases from yeast to neurons. Trends Cell Biol. 16:27–35
    [Google Scholar]
  25. Casamayor A, Torrance PD, Kobayashi T, Thorner J, Alessi DR. 1999. Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast. Curr. Biol. 9:186–97
    [Google Scholar]
  26. Castel P, Dharmaiah S, Sale MJ, Messing S, Rizzuto G et al. 2021. RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity. PNAS 118:e2103261118
    [Google Scholar]
  27. Chen X, Liu M, Tian Y, Li J, Qi Y et al. 2018. Cryo-EM structure of human mTOR complex 2. Cell Res. 28:518–28
    [Google Scholar]
  28. Chiu MI, Katz H, Berlin V. 1994. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. PNAS 91:12574–78
    [Google Scholar]
  29. Colicelli J, Nicolette C, Birchmeier C, Rodgers L, Riggs M, Wigler M. 1991. Expression of three mammalian cDNAs that interfere with RAS function in Saccharomyces cerevisiae. PNAS 88:2913–17
    [Google Scholar]
  30. Consonni SV, Maurice MM, Bos JL. 2014. DEP domains: structurally similar but functionally different. Nat. Rev. Mol. Cell Biol. 15:357–62
    [Google Scholar]
  31. Cui Z, Napolitano G, de Araujo MEG, Esposito A, Monfregola J et al. 2023. Structure of the lysosomal mTORC1–TFEB–Rag–Ragulator megacomplex. Nature 614:572–79
    [Google Scholar]
  32. Daquinag A, Fadri M, Jung SY, Qin J, Kunz J. 2007. The yeast PH domain proteins Slm1 and Slm2 are targets of sphingolipid signaling during the response to heat stress. Mol. Cell. Biol. 27:633–50
    [Google Scholar]
  33. David-Morrison G, Xu Z, Rui YN, Charng WL, Jaiswal M et al. 2016. WAC regulates mTOR activity by acting as an adaptor for the TTT and Pontin/Reptin complexes. Dev. Cell 36:139–51
    [Google Scholar]
  34. Dey P, Su WM, Han GS, Carman GM. 2017. Phosphorylation of lipid metabolic enzymes by yeast protein kinase C requires phosphatidylserine and diacylglycerol. J. Lipid Res. 58:742–51
    [Google Scholar]
  35. Dhillon N, Thorner J. 1996. Immunophilins in the yeast Saccharomyces cerevisiae: a different spin on proline rotamases. Methods 9:165–76
    [Google Scholar]
  36. Dionne U, Gingras AC. 2022. Proximity-dependent biotinylation approaches to explore the dynamic compartmentalized proteome. Front. Mol. Biosci. 9:852911
    [Google Scholar]
  37. Douzery EJ, Snell EA, Bapteste E, Delsuc F, Philippe H. 2004. The timing of eukaryotic evolution: Does a relaxed molecular clock reconcile proteins and fossils?. PNAS 101:15386–91
    [Google Scholar]
  38. Düvel K, Broach JR. 2004. The role of phosphatases in TOR signaling in yeast. Curr. Top. Microbiol. Immunol. 279:19–38
    [Google Scholar]
  39. Ebner M, Sinkovics B, Szczygiel M, Ribeiro DW, Yudushkin I. 2017. Localization of mTORC2 activity inside cells. J. Cell Biol. 216:343–53
    [Google Scholar]
  40. Eltschinger S, Loewith R. 2016. TOR complexes and the maintenance of cellular homeostasis. Trends Cell Biol. 26:148–59
    [Google Scholar]
  41. Fadri M, Daquinag A, Wang S, Xue T, Kunz J. 2005. 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 16:1883–900
    [Google Scholar]
  42. Fu W, Hall MN. 2020. Regulation of mTORC2 signaling. Genes 11:1045
    [Google Scholar]
  43. Fujiyama A, Tsunasawa S, Tamanoi F, Sakiyama F. 1991. S-farnesylation and methyl esterification of C-terminal domain of yeast RAS2 protein prior to fatty acid acylation. J. Biol. Chem. 266:17926–31
    [Google Scholar]
  44. Furuita K, Kataoka S, Sugiki T, Hattori Y, Kobayashi N et al. 2015. Utilization of paramagnetic relaxation enhancements for high-resolution NMR structure determination of a soluble loop-rich protein with sparse NOE distance restraints. J. Biomol. NMR 61:55–64
    [Google Scholar]
  45. Gallego O, Betts MJ, Gvozdenovic-Jeremic J, Maeda K, Matetzki C et al. 2010. A systematic screen for protein-lipid interactions in Saccharomyces cerevisiae. Mol. Syst. Biol. 6:430
    [Google Scholar]
  46. Gan X, Wang J, Wang C, Sommer E, Kozasa T et al. 2012. PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12. Nat. Cell Biol. 14:686–96
    [Google Scholar]
  47. García-Martínez JM, Alessi DR. 2008. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 416:375–85
    [Google Scholar]
  48. Garrenton LS, Stefan CJ, McMurray MA, Emr SD, Thorner J. 2010. Pheromone-induced anisotropy in yeast plasma membrane phosphatidylinositol-4,5-bisphosphate distribution is required for MAPK signaling. PNAS 107:11805–10
    [Google Scholar]
  49. Garrett S, Broach J. 1989. Loss of Ras activity in Saccharomyces cerevisiae is suppressed by disruptions of a new kinase gene, YAK1, whose product may act downstream of the cAMP-dependent protein kinase. Genes Dev. 3:1336–48
    [Google Scholar]
  50. Gatherar M, Pollerman S, Dunn-Coleman N, Turner G. 2004. Identification of a novel gene hbrB required for polarised growth in Aspergillus nidulans. Fungal Genet. Biol. 41:463–71
    [Google Scholar]
  51. Gaubitz C, Oliveira TM, Prouteau M, Leitner A, Karuppasamy M et al. 2015. Molecular basis of the rapamycin insensitivity of Target of Rapamycin Complex 2. Mol. Cell 58:977–88
    [Google Scholar]
  52. Gaubitz C, Prouteau M, Kusmider B, Loewith R. 2016. TORC2 structure and function. Trends Biochem. Sci. 41:532–45
    [Google Scholar]
  53. Goldman A, Roy J, Bodenmiller B, Wanka S, Landry CR et al. 2014. The calcineurin signaling network evolves via conserved kinase-phosphatase modules that transcend substrate identity. Mol. Cell 55:422–35
    [Google Scholar]
  54. González A, Hall MN. 2017. Nutrient sensing and TOR signaling in yeast and mammals. EMBO J. 36:397–408
    [Google Scholar]
  55. González-Rubio G, Sastre-Vergara L, Molina M, Martín H, Fernández-Acero T. 2022. Substrates of the MAPK Slt2: shaping yeast cell integrity. J. Fungi 8:368
    [Google Scholar]
  56. González-Rubio G, Sellers-Moya A, Martín H, Molina M. 2021. A walk-through MAPK structure and functionality with the 30-year-old yeast MAPK Slt2. Int. Microbiol. 24:531–43
    [Google Scholar]
  57. Guerreiro JF, Muir A, Ramachandran S, Thorner J, Sá-Correia I. 2016. Sphingolipid biosynthesis upregulation by TOR complex 2-Ypk1 signaling during yeast adaptive response to acetic acid stress. Biochem. J. 473:4311–25
    [Google Scholar]
  58. Guri Y, Colombi M, Dazert E, Hindupur SK, Roszik J et al. 2017. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell 32:807–23.e12
    [Google Scholar]
  59. Hall MN. 2016. TOR and paradigm change: Cell growth is controlled. Mol. Biol. Cell 27:2804–6
    [Google Scholar]
  60. Heinisch JJ, Rodicio R. 2018. Protein kinase C in fungi—more than just cell wall integrity. FEMS Microbiol. Rev. 42:22–39
    [Google Scholar]
  61. Heitman J, Movva NR, Hall MN. 1991a. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253:905–9
    [Google Scholar]
  62. Heitman J, Movva NR, Hiestand PC, Hall MN. 1991b. FK 506-binding protein proline rotamase is a target for the immunosuppressive agent FK 506 in Saccharomyces cerevisiae. PNAS 88:1948–52
    [Google Scholar]
  63. Helliwell SB, Wagner P, Kunz J, Deuter-Reinhard M, Henriquez R, Hall MN. 1994. TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol. Biol. Cell 5:105–18
    [Google Scholar]
  64. Highland CM, Fromme JC. 2021. Arf1 directly recruits the Pik1-Frq1 PI4K complex to regulate the final stages of Golgi maturation. Mol. Biol. Cell 32:1064–80
    [Google Scholar]
  65. Hill A, Niles B, Cuyegkeng A, Powers T. 2018. Redesigning TOR kinase to explore the structural basis for TORC1 and TORC2 assembly. Biomolecules 8:36
    [Google Scholar]
  66. Ho B, Baryshnikova A, Brown GW. 2018. Unification of protein abundance datasets yields a quantitative Saccharomyces cerevisiae proteome. Cell Syst. 6:192–205.e3
    [Google Scholar]
  67. Ho HL, Lee HY, Liao HC, Chen MY. 2008. Involvement of Saccharomyces cerevisiae Avo3p/Tsc11p in maintaining TOR complex 2 integrity and coupling to downstream signaling. Eukaryot. Cell 7:1328–43
    [Google Scholar]
  68. Hoffman KS, Duennwald ML, Karagiannis J, Genereaux J, McCarton AS, Brandl CJ. 2016. Saccharomyces cerevisiae Tti2 regulates PIKK proteins and stress response. G3 6:1649–59
    [Google Scholar]
  69. Holt LJ, Tuch BB, Villén J, Johnson AD, Gygi SP, Morgan DO. 2009. Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325:1682–86
    [Google Scholar]
  70. Hořejší Z, Stach L, Flower TG, Joshi D, Flynn H et al. 2014. Phosphorylation-dependent PIH1D1 interactions define substrate specificity of the R2TP cochaperone complex. Cell Rep. 7:19–26
    [Google Scholar]
  71. Hořejší Z, Takai H, Adelman CA, Collis SJ, Flynn H et al. 2010. CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability. Mol. Cell 39:839–50
    [Google Scholar]
  72. Houry WA, Bertrand E, Coulombe B. 2018. The PAQosome, an R2TP-based chaperone for quaternary structure formation. Trends Biochem. Sci. 43:4–9
    [Google Scholar]
  73. Huang J, Manning BD. 2009. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem. Soc. Trans. 37:217–22
    [Google Scholar]
  74. Ikai N, Nakazawa N, Hayashi T, Yanagida M. 2011. The reverse, but coordinated, roles of Tor2 (TORC1) and Tor1 (TORC2) kinases for growth, cell cycle and separase-mediated mitosis in Schizosaccharomyces pombe. Open Biol. 1:110007
    [Google Scholar]
  75. Ito T, Chiba T, Ozawa R, Yoshida M, Hattori M, Sakaki Y. 2001. A comprehensive two-hybrid analysis to explore the yeast protein interactome. PNAS 98:4569–74
    [Google Scholar]
  76. Izumi N, Yamashita A, Ohno S. 2012. Integrated regulation of PIKK-mediated stress responses by AAA+ proteins RUVBL1 and RUVBL2. Nucleus 3:29–43
    [Google Scholar]
  77. Jacinto E, Guo B, Arndt KT, Schmelzle T, Hall MN 2001. TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway. Mol. Cell 8:1017–26
    [Google Scholar]
  78. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA et al. 2004. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6:1122–28
    [Google Scholar]
  79. Jang H, Park Y, Jang J. 2022. Serum and glucocorticoid-regulated kinase 1: structure, biological functions, and its inhibitors. Front. Pharmacol. 13:1036844
    [Google Scholar]
  80. Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K et al. 2010. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J. Biol. Chem. 285:20109–16
    [Google Scholar]
  81. Kamano Y, Saeki M, Egusa H, Kakihara Y, Houry WA et al. 2013. PIH1D1 interacts with mTOR complex 1 and enhances ribosome RNA transcription. FEBS Lett. 587:3303–08
    [Google Scholar]
  82. Kamble C, Jain S, Murphy E, Kim K. 2011. Requirements of Slm proteins for proper eisosome organization, endocytic trafficking and recycling in the yeast Saccharomyces cerevisiae. J. Biosci. 36:79–96
    [Google Scholar]
  83. Karotki L, Huiskonen JT, Stefan CJ, Ziółkowska NE, Roth R et al. 2011. Eisosome proteins assemble into a membrane scaffold. J. Cell Biol. 195:889–902
    [Google Scholar]
  84. Karuppasamy M, Kusmider B, Oliveira TM, Gaubitz C, Prouteau M et al. 2017. Cryo-EM structure of Saccharomyces cerevisiae target of rapamycin complex 2. Nat. Commun. 8:1729
    [Google Scholar]
  85. Kataoka S, Furuita K, Hattori Y, Kobayashi N, Ikegami T et al. 2015. 1H, 15N and 13C resonance assignments of the conserved region in the middle domain of S. pombe Sin1 protein. Biomol. NMR Assign. 9:89–92
    [Google Scholar]
  86. Kataoka T, Powers S, McGill C, Fasano O, Strathern J et al. 1984. Genetic analysis of yeast RAS1 and RAS2 genes. Cell 37:437–45
    [Google Scholar]
  87. Kennedy MA, Gable K, Niewola-Staszkowska K, Abreu S, Johnston A et al. 2014. A neurotoxic glycerophosphocholine impacts PtdIns-4, 5-bisphosphate and TORC2 signaling by altering ceramide biosynthesis in yeast. PLOS Genet. 10:e1004010
    [Google Scholar]
  88. Khanna A, Lotfi P, Chavan AJ, Montaño NM, Bolourani P et al. 2016. The small GTPases Ras and Rap1 bind to and control TORC2 activity. Sci. Rep. 6:25823
    [Google Scholar]
  89. Kim J, Guan KL. 2019. mTOR as a central hub of nutrient signalling and cell growth. Nat. Cell Biol. 21:63–71
    [Google Scholar]
  90. Kim SG, Hoffman GR, Poulogiannis G, Buel GR, Jang YJ et al. 2013. Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol. Cell 49:172–85
    [Google Scholar]
  91. Kolakowski D, Rzepnikowska W, Kaniak-Golik A, Zoladek T, Kaminska J. 2021. The GTPase Arf1 is a determinant of yeast Vps13 localization to the Golgi apparatus. Int. J. Mol. Sci. 22:12274
    [Google Scholar]
  92. Koltin Y, Faucette L, Bergsma DJ, Levy MA, Cafferkey R et al. 1991. Rapamycin sensitivity in Saccharomycescerevisiae is mediated by a peptidyl-prolyl cis-trans isomerase related to human FK506-binding protein. Mol. Cell. Biol. 11:1718–23
    [Google Scholar]
  93. Kovalski JR, Bhaduri A, Zehnder AM, Neela PH, Che Y et al. 2019. The functional proximal proteome of oncogenic Ras includes mTORC2. Mol. Cell 73:830–44.e12
    [Google Scholar]
  94. Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, Hall MN. 1993. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73:585–96
    [Google Scholar]
  95. Kunz J, Schneider U, Howald I, Schmidt A, Hall MN. 2000. HEAT repeats mediate plasma membrane localization of Tor2p in yeast. J. Biol. Chem. 275:37011–20
    [Google Scholar]
  96. Lanz MC, Yugandhar K, Gupta S, Sanford EJ, Faça VM et al. 2021. In-depth and 3-dimensional exploration of the budding yeast phosphoproteome. EMBO Rep. 22:e51121
    [Google Scholar]
  97. Lanze CE, Gandra RM, Foderaro JE, Swenson KA, Douglas LM, Konopka JB. 2020. Plasma membrane MCC/eisosome domains promote stress resistance in fungi. Microbiol. Mol. Biol. Rev. 84:e00063-19
    [Google Scholar]
  98. Lawrence RE, Zoncu R. 2019. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat. Cell Biol. 21:133–42
    [Google Scholar]
  99. Lee J, Liu L, Levin DE. 2019. Stressing out or stressing in: intracellular pathways for SAPK activation. Curr. Genet. 65:417–21
    [Google Scholar]
  100. Lee S, Parent CA, Insall R, Firtel RA. 1999. A novel Ras-interacting protein required for chemotaxis and cyclic adenosine monophosphate signal relay in Dictyostelium. Mol. Biol. Cell 10:2829–45
    [Google Scholar]
  101. Lee YJ, Jeschke GR, Roelants FM, Thorner J, Turk BE. 2012. Reciprocal phosphorylation of yeast glycerol-3-phosphate dehydrogenases in adaptation to distinct types of stress. Mol. Cell. Biol. 32:4705–17
    [Google Scholar]
  102. Leskoske KL, Roelants FM, Emmerstorfer-Augustin A, Augustin CM, Si EP et al. 2018. Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2. Genes Dev. 32:1576–90
    [Google Scholar]
  103. Leskoske KL, Roelants FM, Marshall MNM, Hill JM, Thorner J. 2017. The stress-sensing TORC2 complex activates yeast AGC-family protein kinase Ypk1 at multiple novel sites. Genetics 207:179–95
    [Google Scholar]
  104. Levin DE. 2011. Regulation of cell wall biogenesis in Saccharomyces cerevisiae: the cell wall integrity signaling pathway. Genetics 189:1145–75
    [Google Scholar]
  105. Levin DE, Fields FO, Kunisawa R, Bishop JM, Thorner J. 1990. A candidate protein kinase C gene, PKC1, is required for the S. cerevisiae cell cycle. Cell 62:213–24
    [Google Scholar]
  106. Li J, Yan G, Liu S, Jiang T, Zhong M et al. 2017. Target of rapamycin complex 1 and Tap42-associated phosphatases are required for sensing changes in nitrogen conditions in the yeast Saccharomyces cerevisiae. Mol. Microbiol. 106:938–48
    [Google Scholar]
  107. Li T, Chen X, Dai XY, Wei B, Weng QJ et al. 2017. Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor. Toxicol. Appl. Pharmacol. 330:65–73
    [Google Scholar]
  108. Liao HC, Chen MY. 2012. 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. 287:6089–99
    [Google Scholar]
  109. Linder ME, Deschenes RJ. 2007. Palmitoylation: policing protein stability and traffic. Nat. Rev. Mol. Cell Biol. 8:74–84
    [Google Scholar]
  110. Liu GY, Sabatini DM. 2020. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21:183–203
    [Google Scholar]
  111. Liu P, Gan W, Chin YR, Ogura K, Guo J et al. 2015. PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov. 5:1194–209
    [Google Scholar]
  112. Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D et al. 2013. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat. Cell Biol. 15:1340–50
    [Google Scholar]
  113. Livi GP. 2019. Halcyon days of TOR: reflections on the multiple independent discovery of the yeast and mammalian TOR proteins. Gene 692:145–55
    [Google Scholar]
  114. Locke MN, Thorner J. 2019a. Rab5 GTPases are required for optimal TORC2 function. J. Cell Biol. 218:961–76
    [Google Scholar]
  115. Locke MN, Thorner J. 2019b. Regulation of TORC2 function and localization by Rab5 GTPases in Saccharomyces cerevisiae. Cell Cycle 18:1084–94
    [Google Scholar]
  116. Loewith R, Hall MN. 2011. Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189:1177–201
    [Google Scholar]
  117. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL et al. 2002. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10:457–68
    [Google Scholar]
  118. Lu M, Wang J, Ives HE, Pearce D. 2011. mSIN1 protein mediates SGK1 protein interaction with mTORC2 protein complex and is required for selective activation of the epithelial sodium channel. J. Biol. Chem. 286:30647–54
    [Google Scholar]
  119. Luciano AK, Korobkina ED, Lyons SP, Haley JA, Fluharty SM et al. 2022. Proximity labeling of endogenous RICTOR identifies mTOR complex 2 regulation by ADP ribosylation factor ARF1. J. Biol. Chem. 298:102379
    [Google Scholar]
  120. Lynham J, Houry WA. 2022. The role of Hsp90-R2TP in macromolecular complex assembly and stabilization. Biomolecules 12:1045
    [Google Scholar]
  121. MacGilvray ME, Shishkova E, Place M, Wagner ER, Coon JJ, Gasch AP. 2020. Phosphoproteome response to dithiothreitol reveals unique versus shared features of Saccharomyces cerevisiae stress responses. J. Proteome Res. 19:3405–17
    [Google Scholar]
  122. Martinez Marshall MN, Emmerstorfer-Augustin A, Leskoske KL, Zhang LH, Li B, Thorner J 2019. Analysis of the roles of phosphatidylinositol-4,5-bisphosphate and individual subunits in assembly, localization, and function of Saccharomyces cerevisiae target of rapamycin complex 2. Mol. Biol. Cell 30:1555–74
    [Google Scholar]
  123. Moseley JB. 2018. Eisosomes. Curr. Biol. 28:R376–78
    [Google Scholar]
  124. Muir A, Ramachandran S, Roelants FM, Timmons G, Thorner J. 2014. TORC2-dependent protein kinase Ypk1 phosphorylates ceramide synthase to stimulate synthesis of complex sphingolipids. eLife 3:e03779
    [Google Scholar]
  125. Muir A, Roelants FM, Timmons G, Leskoske KL, Thorner J. 2015. Down-regulation of TORC2-Ypk1 signaling promotes MAPK-independent survival under hyperosmotic stress. eLife 4:e09336
    [Google Scholar]
  126. Murley A, Yamada J, Niles BJ, Toulmay A, Prinz WA et al. 2017. Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling. J. Cell Biol. 216:2679–89
    [Google Scholar]
  127. Nicastro R, Sardu A, Panchaud N, De Virgilio C. 2017. The architecture of the Rag GTPase signaling network. Biomolecules 7:48
    [Google Scholar]
  128. Niles BJ, Mogri H, Hill A, Vlahakis A, Powers T. 2012. 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. PNAS 109:1536–41
    [Google Scholar]
  129. Niles BJ, Powers T. 2012. Plasma membrane proteins Slm1 and Slm2 mediate activation of the AGC kinase Ypk1 by TORC2 and sphingolipids in S. cerevisiae. Cell Cycle 11:3745–49
    [Google Scholar]
  130. Nishimura K, Fukagawa T, Takisawa H, Kakimoto T, Kanemaki M. 2009. An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat. Methods 6:917–22
    [Google Scholar]
  131. Nomura W, Ito Y, Inoue Y. 2017. Role of phosphatidylserine in the activation of Rho1-related Pkc1 signaling in Saccharomyces cerevisiae. Cell. Signal. 31:146–53
    [Google Scholar]
  132. Olivera-Couto A, Graña M, Harispe L, Aguilar PS. 2011. The eisosome core is composed of BAR domain proteins. Mol. Biol. Cell 22:2360–72
    [Google Scholar]
  133. Pal M, Muñoz-Hernandez H, Bjorklund D, Zhou L, Degliesposti G et al. 2021. Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone. Cell Rep. 36:109317
    [Google Scholar]
  134. Pan D, Matsuura Y. 2012. Structures of the pleckstrin homology domain of Saccharomyces cerevisiae Avo1 and its human orthologue Sin1, an essential subunit of TOR complex 2. Acta Crystallogr. F 68:386–92
    [Google Scholar]
  135. Pearce LR, Komander D, Alessi DR. 2010. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 11:9–22
    [Google Scholar]
  136. Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR. 2011. Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem. J. 436:169–79
    [Google Scholar]
  137. Pemberton TJ, Kay JE. 2005. Identification and comparative analysis of the peptidyl-prolyl cis/trans isomerase repertoires of H. sapiens, D. melanogaster, C. elegans, S. cerevisiae and Sz. pombe. Comp. Funct. Genom. 6:277–300
    [Google Scholar]
  138. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA et al. 2009. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137:873–86
    [Google Scholar]
  139. Pontes B, Monzo P, Gauthier NC. 2017. Membrane tension: a challenging but universal physical parameter in cell biology. Semin. Cell Dev. Biol. 71:30–41
    [Google Scholar]
  140. Powers T. 2022. The origin story of rapamycin: systemic bias in biomedical research and cold war politics. Mol. Biol. Cell 33:pe7
    [Google Scholar]
  141. Pracheil T, Thornton J, Liu Z. 2012. TORC2 signaling is antagonized by protein phosphatase 2A and the Far complex in Saccharomyces cerevisiae. Genetics 190:1325–39
    [Google Scholar]
  142. Prodromou C, Bjorklund DM. 2022. Advances towards understanding the mechanism of action of the Hsp90 complex. Biomolecules 12:600
    [Google Scholar]
  143. Pudewell S, Lissy J, Nakhaeizadeh H, Mosaddeghzadeh N, Nakhaei-Rad S et al. 2022. New mechanistic insights into the RAS-SIN1 interaction at the membrane. Front. Cell Dev. Biol. 10:987754
    [Google Scholar]
  144. Riggi M, Kusmider B, Loewith R. 2020. The flipside of the TOR coin – TORC2 and plasma membrane homeostasis at a glance. J. Cell Sci. 133:jcs242040
    [Google Scholar]
  145. Riggi M, Niewola-Staszkowska K, Chiaruttini N, Colom A, Kusmider B et al. 2018. Decrease in plasma membrane tension triggers PtdIns(4,5)P2 phase separation to inactivate TORC2. Nat. Cell Biol. 20:1043–51
    [Google Scholar]
  146. Roelants FM, Breslow DK, Muir A, Weissman JS, Thorner J. 2011. Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae. PNAS 108:19222–27
    [Google Scholar]
  147. Roelants FM, Leskoske KL, Martinez Marshall MN, Locke MN, Thorner J 2017. The TORC2-dependent signaling network in the yeast Saccharomyces cerevisiae. Biomolecules 7:66
    [Google Scholar]
  148. Roelants FM, Torrance PD, Bezman N, Thorner J. 2002. Pkh1 and Pkh2 differentially phosphorylate and activate Ypk1 and Ykr2 and define protein kinase modules required for maintenance of cell wall integrity. Mol. Biol. Cell 13:3005–28
    [Google Scholar]
  149. Roelants FM, Torrance PD, Thorner J. 2004. Differential roles of PDK1- and PDK2-phosphorylation sites in the yeast AGC kinases Ypk1, Pkc1 and Sch9. Microbiology 150:3289–304
    [Google Scholar]
  150. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. 1994. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43
    [Google Scholar]
  151. Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ et al. 1995. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270:815–22
    [Google Scholar]
  152. Sakata KT, Hashii K, Yoshizawa K, Tahara YO, Yae K et al. 2022. Coordinated regulation of TORC2 signaling by MCC/eisosome-associated proteins, Pil1 and tetraspan membrane proteins during the stress response. Mol. Microbiol. 117:1227–44
    [Google Scholar]
  153. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303
    [Google Scholar]
  154. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR et al. 2004. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14:1296–302
    [Google Scholar]
  155. Sarbassov DD, Ali SM, Sabatini DM. 2005. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17:596–603
    [Google Scholar]
  156. Saxton RA, Sabatini DM. 2017. mTOR signaling in growth, metabolism, and disease. Cell 168:960–76
    [Google Scholar]
  157. Scaiola A, Mangia F, Imseng S, Boehringer D, Berneiser K et al. 2020. The 3.2-Å resolution structure of human mTORC2. Sci. Adv. 6:eabc1251
    [Google Scholar]
  158. Schmelzle T, Beck T, Martin DE, Hall MN. 2004. Activation of the RAS/cyclic AMP pathway suppresses a TOR deficiency in yeast. Mol. Cell. Biol. 24:338–51
    [Google Scholar]
  159. Schreiber SL. 1991. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science 251:283–87
    [Google Scholar]
  160. Schroder WA, Buck M, Cloonan N, Hancock JF, Suhrbier A et al. 2007. Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling. Cell Signal. 19:1279–89
    [Google Scholar]
  161. Sehgal SN. 2003. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant. Proc. 35:Suppl. 37S–14S
    [Google Scholar]
  162. Shertz CA, Bastidas RJ, Li W, Heitman J, Cardenas ME 2010. Conservation, duplication, and loss of the Tor signaling pathway in the fungal kingdom. BMC Genom. 23:510
    [Google Scholar]
  163. Shioda R. 2006. Functional analysis of TOR complex 2 and its control of sphingolipid biosynthesis in Saccharomyces cerevisiae PhD Diss. Univ. Basel Basel, Switz:.
    [Google Scholar]
  164. Sturgill TW, Cohen A, Diefenbacher M, Trautwein M, Martin DE, Hall MN. 2008. TOR1 and TOR2 have distinct locations in live cells. Eukaryot. Cell 7:1819–30
    [Google Scholar]
  165. Stuttfeld E, Aylett CHS, Imseng S, Boehringer D, Scaiola A et al. 2018. Architecture of the human mTORC2 core complex. eLife 7:e33101
    [Google Scholar]
  166. Sugimoto K. 2018. Branching the Tel2 pathway for exact fit on phosphatidylinositol 3-kinase-related kinases. Curr. Genet. 64:965–70
    [Google Scholar]
  167. Sun J, Kale SP, Childress AM, Pinswasdi C, Jazwinski SM. 1994. Divergent roles of RAS1 and RAS2 in yeast longevity. J. Biol. Chem. 269:18638–45
    [Google Scholar]
  168. Swaney DL, Beltrao P, Starita L, Guo A, Rush J et al. 2013. Global analysis of phosphorylation and ubiquitylation cross-talk in protein degradation. Nat. Methods 10:676–82
    [Google Scholar]
  169. Tabuchi M, Audhya A, Parsons AB, Boone C, Emr SD. 2006. The phosphatidylinositol 4,5-biphosphate and TORC2 binding proteins Slm1 and Slm2 function in sphingolipid regulation. Mol. Cell. Biol. 26:5861–75
    [Google Scholar]
  170. Tafur L, Kefauver J, Loewith R. 2020. Structural insights into TOR signaling. Genes 11:885
    [Google Scholar]
  171. Takai H, Xie Y, de Lange T, Pavletich NP. 2010. Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes. Genes Dev. 24:2019–30
    [Google Scholar]
  172. Tatebe H, Murayama S, Yonekura T, Hatano T, Richter D et al. 2017. Substrate specificity of TOR complex 2 is determined by a ubiquitin-fold domain of the Sin1 subunit. eLife 6:e19594
    [Google Scholar]
  173. Thorner J. 2022. TOR complex 2 is a master regulator of plasma membrane homeostasis. Biochem. J. 479:1917–40
    [Google Scholar]
  174. Tsverov J, Yegorov K, Powers T. 2022. Identification of defined structural elements within TOR2 kinase required for TOR complex 2 assembly and function in Saccharomyces cerevisiae. Mol. Biol. Cell 33:ar44
    [Google Scholar]
  175. Uetz P, Giot L, Cagney G, Mansfield TA, Judson RS et al. 2000. A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae. Nature 403:623–27
    [Google Scholar]
  176. Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D et al. 2007. Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol. Cell 26:663–74
    [Google Scholar]
  177. Van Aelst L, White MA, Wigler MH. 1994. Ras partners. Cold Spring Harb. Symp. Quant. Biol. 59:181–86
    [Google Scholar]
  178. Varadi M, Anyango S, Deshpande M, Nair S, Natassia C et al. 2022. AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50:D1D439–44
    [Google Scholar]
  179. Vézina C, Kudelski A, Sehgal SN. 1975. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28:721–26
    [Google Scholar]
  180. Wälchli M, Berneiser K, Mangia F, Imseng S, Craigie LM et al. 2021. Regulation of human mTOR complexes by DEPTOR. eLife 10:e70871
    [Google Scholar]
  181. Wandinger-Ness A, Zerial M. 2014. Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harb. Perspect. Biol. 6:a022616
    [Google Scholar]
  182. Wedaman KP, Reinke A, Anderson S, Yates J, McCaffery JM, Powers T. 2003. Tor kinases are in distinct membrane-associated protein complexes in Saccharomyces cerevisiae. Mol. Biol. Cell 14:1204–20
    [Google Scholar]
  183. Weng Z, Shen X, Zheng J, Liang H, Liu Y. 2021. Structural basis of DEPTOR to recognize phosphatidic acid using its tandem DEP domains. J. Mol. Biol. 433:166989
    [Google Scholar]
  184. Woodman PG. 2000. Biogenesis of the sorting endosome: the role of Rab5. Traffic 1:695–701
    [Google Scholar]
  185. Wullschleger S, Loewith R, Oppliger W, Hall MN. 2005. Molecular organization of target of rapamycin complex 2. J. Biol. Chem. 280:30697–704
    [Google Scholar]
  186. Yaffe MB, Leparc GG, Lai J, Obata T, Volinia S, Cantley LC. 2001. A motif-based profile scanning approach for genome-wide prediction of signaling pathways. Nat. Biotechnol. 19:348–53
    [Google Scholar]
  187. Yang H, Jiang X, Li B, Yang HJ, Miller M et al. 2017. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552:368–73
    [Google Scholar]
  188. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. 2013. mTOR kinase structure, mechanism and regulation. Nature 497:217–23
    [Google Scholar]
  189. Yang Q, Inoki K, Ikenoue T, Guan KL. 2006. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20:2820–32
    [Google Scholar]
  190. Ye L, Varamini B, Lamming DW, Sabatini DM, Baur JA. 2012. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front. Genet. 3:177
    [Google Scholar]
  191. Yu Z, Chen J, Takagi E, Wang F, Saha B et al. 2022. Interactions between mTORC2 core subunits Rictor and mSin1 dictate selective and context-dependent phosphorylation of substrate kinases SGK1 and Akt. J. Biol. Chem. 298:102288
    [Google Scholar]
  192. Zheng Y, Ding L, Meng X, Potter M, Kearney AL et al. 2022. Structural insights into Ras regulation by SIN1. PNAS 119:e2119990119
    [Google Scholar]
/content/journals/10.1146/annurev-cellbio-011723-030346
Loading
/content/journals/10.1146/annurev-cellbio-011723-030346
Loading

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error