BACKGROUND: The protein kinase Target Of Rapamycin (TOR) is a nexus for the regulation of eukaryotic cell growth. TOR assembles into one of two distinct signalling complexes, TOR complex 1 (TORC1) and TORC2 (mTORC1/2 in mammals), with a set of largely non-overlapping protein partners. (m)TORC1 activation occurs in response to a series of stimuli relevant to cell growth, including nutrient availability, growth factor signals and stress, and regulates much of the cell’s biosynthetic activity, from proteins to lipids, and recycling through autophagy. mTORC1 regulation is of great therapeutic significance, since in humans many of these signalling complexes, alongside subunits of mTORC1 itself, are implicated in a wide variety of pathophysiologies, including multiple types of cancer, neurological disorders, neurodegenerative diseases and metabolic disorders including diabetes.
METHODOLOGY: Recent years have seen numerous structures determined of (m)TOR, which have provided mechanistic insight into (m)TORC1 activation in particular, however the integration of cellular signals occurs upstream of the kinase and remains incompletely understood. Here we have collected and analysed in detail as many as possible of the molecular and structural studies which have shed light on (m)TORC1 repression, activation and signal integration.
CONCLUSIONS: A molecular understanding of this signal integration pathway is required to understand how (m)TORC1 activation is reconciled with the many diverse and contradictory stimuli affecting cell growth. We discuss the current level of molecular understanding of the upstream components of the (m)TORC1 signalling pathway, recent progress on this key biochemical frontier, and the future studies necessary to establish a mechanistic understanding of this master-switch for eukaryotic cell growth.
. [J]. Frontiers in Biology, 2018, 13(4): 237-262.
Kailash Ramlaul, Christopher H. S. Aylett. Signal integration in the (m)TORC1 growth pathway. Front. Biol., 2018, 13(4): 237-262.
Algret R, Fernandez-Martinez J, Shi Y, Kim S J, Pellarin R, Cimermancic P, Cochet E, Sali A, Chait B T, Rout M P, Dokudovskaya S (2014). Molecular architecture and function of the SEA complex, a modulator of the TORC1 pathway. Mol Cell Proteomics, 13(11): 2855–2870 https://doi.org/10.1074/mcp.M114.039388
pmid: 25073740
2
Aylett C H S, Sauer E, Imseng S, Boehringer D, Hall M N, Ban N, Maier T (2016). Architecture of human mTOR complex 1. Science, 351(6268): 48–52 https://doi.org/10.1126/science.aaa3870
pmid: 26678875
3
Baba M, Hong S B, Sharma N, Warren M B, Nickerson M L, Iwamatsu A, Esposito D, Gillette W K, Hopkins R F3rd, Hartley J L, Furihata M, Oishi S, Zhen W, Burke T RJr, Linehan W M, Schmidt L S, Zbar B (2006). Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci USA, 103(42): 15552–15557 https://doi.org/10.1073/pnas.0603781103
pmid: 17028174
4
Baldassari S, Licchetta L, Tinuper P, Bisulli F, Pippucci T (2016). GATOR1 complex: the common genetic actor in focal epilepsies. J Med Genet, 53(8): 503–510 https://doi.org/10.1136/jmedgenet-2016-103883
pmid: 27208208
5
Balderhaar H J, Ungermann C (2013). CORVET and HOPS tethering complexes- coordinators of endosome and lysosome fusion. J Cell Sci, 126(Pt 6): 1307–1316 https://doi.org/10.1242/jcs.107805
pmid: 23645161
6
Baple E L, Maroofian R, Chioza B A, Izadi M, Cross H E, Al-Turki S, Barwick K, Skrzypiec A, Pawlak R, Wagner K, Coblentz R, Zainy T, Patton M A, Mansour S, Rich P, Qualmann B, Hurles M E, Kessels M M, Crosby A H (2014). Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures. Am J Hum Genet, 94(1): 87–94 https://doi.org/10.1016/j.ajhg.2013.10.001
pmid: 24239382
7
Bar-Peled L, Chantranupong L, Cherniack A D, Chen W W, Ottina K A, Grabiner B C, Spear E D, Carter S L, Meyerson M, Sabatini D M (2013). A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science, 340(6136): 1100–1106 https://doi.org/10.1126/science.1232044
pmid: 23723238
8
Bar-Peled L, Schweitzer L D, Zoncu R, Sabatini D M (2012). Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell, 150(6): 1196–1208 https://doi.org/10.1016/j.cell.2012.07.032
pmid: 22980980
9
Baretić D, Berndt A, Ohashi Y, Johnson C M, Williams R L (2016). Tor forms a dimer through an N-terminal helical solenoid with a complex topology. Nat Commun, 7: 11016 https://doi.org/10.1038/ncomms11016
pmid: 27072897
10
Basel-Vanagaite L, Hershkovitz T, Heyman E, Raspall-Chaure M, Kakar N, Smirin-Yosef P, Vila-Pueyo M, Kornreich L, Thiele H, Bode H, Lagovsky I, Dahary D, Haviv A, Hubshman M W, Pasmanik-Chor M, Nürnberg P, Gothelf D, Kubisch C, Shohat M, Macaya A, Borck G (2013). Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am J Hum Genet, 93(3): 524–529 https://doi.org/10.1016/j.ajhg.2013.07.005
pmid: 23932106
Bharucha N, Liu Y, Papanikou E, McMahon C, Esaki M, Jeffrey P D, Hughson F M, Glick B S (2013). Sec16 influences transitional ER sites by regulating rather than organizing COPII. Mol Biol Cell, 24(21): 3406–3419 https://doi.org/10.1091/mbc.e13-04-0185
pmid: 24006484
13
Blommaart E F, Luiken J J, Blommaart P J, van Woerkom G M, Meijer A J (1995). Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem, 270(5): 2320–2326 https://doi.org/10.1074/jbc.270.5.2320
pmid: 7836465
Brohawn S G, Leksa N C, Spear E D, Rajashankar K R, Schwartz T U (2008). Structural evidence for common ancestry of the nuclear pore complex and vesicle coats. Science, 322(5906): 1369–1373 https://doi.org/10.1126/science.1165886
pmid: 18974315
16
Brohawn S G, Schwartz T U (2009). Molecular architecture of the Nup84-Nup145C-Sec13 edge element in the nuclear pore complex lattice. Nat Struct Mol Biol, 16(11): 1173–1177 https://doi.org/10.1038/nsmb.1713
pmid: 19855394
17
Brown E J, Albers M W, Shin T B, Ichikawa K, Keith C T, Lane W S, Schreiber S L (1994). A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature, 369(6483): 756–758 https://doi.org/10.1038/369756a0
pmid: 8008069
18
Brugarolas J, Lei K, Hurley R L, Manning B D, Reiling J H, Hafen E, Witters L A, Ellisen L W, Kaelin W GJr (2004). Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev, 18(23): 2893–2904 https://doi.org/10.1101/gad.1256804
pmid: 15545625
Budanov A V, Shoshani T, Faerman A, Zelin E, Kamer I, Kalinski H, Gorodin S, Fishman A, Chajut A, Einat P, Skaliter R, Gudkov A V, Chumakov P M, Feinstein E (2002). Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene, 21(39): 6017–6031 https://doi.org/10.1038/sj.onc.1205877
pmid: 12203114
21
Buerger C, DeVries B, Stambolic V (2006). Localization of Rheb to the endomembrane is critical for its signaling function. Biochem Biophys Res Commun, 344(3): 869–880 https://doi.org/10.1016/j.bbrc.2006.03.220
pmid: 16631613
22
Bun-Ya M, Harashima S, Oshima Y (1992). Putative GTP-binding protein, Gtr1, associated with the function of the Pho84 inorganic phosphate transporter in Saccharomyces cerevisiae. Mol Cell Biol, 12(7): 2958–2966 https://doi.org/10.1128/MCB.12.7.2958
pmid: 1620108
23
Burnett P E, Barrow R K, Cohen N A, Snyder S H, Sabatini D M (1998). RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA, 95(4): 1432–1437 https://doi.org/10.1073/pnas.95.4.1432
pmid: 9465032
24
Cai S L, Tee A R, Short J D, Bergeron J M, Kim J, Shen J, Guo R, Johnson C L, Kiguchi K, Walker C L (2006). Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J Cell Biol, 173(2): 279–289 https://doi.org/10.1083/jcb.200507119
pmid: 16636147
25
Castellano B M, Thelen A M, Moldavski O, Feltes M, van der Welle R E N, Mydock-McGrane L, Jiang X, van Eijkeren R J, Davis O B, Louie S M, Perera R M, Covey D F, Nomura D K, Ory D S, Zoncu R (2017). Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science, 355(6331): 1306–1311 https://doi.org/10.1126/science.aag1417
pmid: 28336668
26
Castro A F, Rebhun J F, Clark G J, Quilliam L A (2003). Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem, 278(35): 32493–32496 https://doi.org/10.1074/jbc.C300226200
pmid: 12842888
27
Chantranupong L, Scaria S M, Saxton R A, Gygi M P, Shen K, Wyant G A, Wang T, Harper J W, Gygi S P, Sabatini D M (2016). The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. Cell, 165(1): 153–164 https://doi.org/10.1016/j.cell.2016.02.035
pmid: 26972053
28
Chantranupong L, Wolfson R L, Orozco J M, Saxton R A, Scaria S M, Bar-Peled L, Spooner E, Isasa M, Gygi S P, Sabatini D M (2014). The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Reports, 9(1): 1–8 https://doi.org/10.1016/j.celrep.2014.09.014
pmid: 25263562
29
Chen E J, Kaiser C A (2003). LST8 negatively regulates amino acid biosynthesis as a component of the TOR pathway. J Cell Biol, 161(2): 333–347 https://doi.org/10.1083/jcb.200210141
pmid: 12719473
30
Chen J, Zheng X F, Brown E J, Schreiber S L (1995). Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci USA, 92(11): 4947–4951 https://doi.org/10.1073/pnas.92.11.4947
pmid: 7539137
Chiu M I, Katz H, Berlin V (1994). RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA, 91(26): 12574–12578 https://doi.org/10.1073/pnas.91.26.12574
pmid: 7809080
33
Clark G J, Kinch M S, Rogers-Graham K, Sebti S M, Hamilton A D, Der C J (1997). The Ras-related protein Rheb is farnesylated and antagonizes Ras signaling and transformation. J Biol Chem, 272(16): 10608–10615 https://doi.org/10.1074/jbc.272.16.10608
pmid: 9099708
34
Cui Q, Sulea T, Schrag J D, Munger C, Hung M N, Naïm M, Cygler M, Purisima E O (2008). Molecular dynamics-solvated interaction energy studies of protein-protein interactions: the MP1-p14 scaffolding complex. J Mol Biol, 379(4): 787–802 https://doi.org/10.1016/j.jmb.2008.04.035
pmid: 18479705
de Araujo M E G, Naschberger A, Fürnrohr B G, Stasyk T, Dunzendorfer-Matt T, Lechner S, Welti S, Kremser L, Shivalingaiah G, Offterdinger M, Lindner H H, Huber L A, Scheffzek K (2017). Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling. Science, 358(6361): 377–381 https://doi.org/10.1126/science.aao1583
pmid: 28935770
37
De Franceschi N, Wild K, Schlacht A, Dacks J B, Sinning I, Filippini F (2014). Longin and GAF domains: structural evolution and adaptation to the subcellular trafficking machinery. Traffic, 15(1): 104–121 https://doi.org/10.1111/tra.12124
pmid: 24107188
38
Debler E W, Ma Y, Seo H S, Hsia K C, Noriega T R, Blobel G, Hoelz A (2008). A fence-like coat for the nuclear pore membrane. Mol Cell, 32(6): 815–826 https://doi.org/10.1016/j.molcel.2008.12.001
pmid: 19111661
39
Demetriades C, Plescher M, Teleman A A (2016). Lysosomal recruitment of TSC2 is a universal response to cellular stress. Nat Commun, 7: 10662 https://doi.org/10.1038/ncomms10662
pmid: 26868506
40
Deng Y, Qin Y, Srikantan S, Luo A, Cheng Z M, Flores S K, Vogel K S, Wang E, Dahia P L M (2018). The TMEM127 human tumor suppressor is a component of the mTORC1 lysosomal nutrient-sensing complex. Hum Mol Genet, 27(10): 1794–1808 https://doi.org/10.1093/hmg/ddy095
pmid: 29547888
41
DeYoung M P, Horak P, Sofer A, Sgroi D, Ellisen L W (2008). Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev, 22(2): 239–251 https://doi.org/10.1101/gad.1617608
pmid: 18198340
42
Dibble C C, Elis W, Menon S, Qin W, Klekota J, Asara J M, Finan P M, Kwiatkowski D J, Murphy L O, Manning B D (2012). TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell, 47(4): 535–546 https://doi.org/10.1016/j.molcel.2012.06.009
pmid: 22795129
Dokudovskaya S, Waharte F, Schlessinger A, Pieper U, Devos D P, Cristea I M, Williams R, Salamero J, Chait B T, Sali A, Field M C, Rout M P, Dargemont C(2011). A conserved coatomer-related complex containing Sec13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae. Mol. Cell Proteomics 10, M110.006478. doi:10.1074/mcp.M110.006478
45
Dubouloz F, Deloche O, Wanke V, Cameroni E, De Virgilio C (2005). The TOR and EGO protein complexes orchestrate microautophagy in yeast. Mol Cell, 19(1): 15–26 https://doi.org/10.1016/j.molcel.2005.05.020
pmid: 15989961
Faini M, Beck R, Wieland F T, Briggs J A G (2013). Vesicle coats: structure, function, and general principles of assembly. Trends Cell Biol, 23(6): 279–288 https://doi.org/10.1016/j.tcb.2013.01.005
pmid: 23414967
Filipek P A, de Araujo M E G, Vogel G F, De Smet C H, Eberharter D, Rebsamen M, Rudashevskaya E L, Kremser L, Yordanov T, Tschaikner P, Fürnrohr B G, Lechner S, Dunzendorfer-Matt T, Scheffzek K, Bennett K L, Superti-Furga G, Lindner H H, Stasyk T, Huber L A (2017). LAMTOR/Ragulator is a negative regulator of Arl8b- and BORC-dependent late endosomal positioning. J Cell Biol, 216(12): 4199–4215 https://doi.org/10.1083/jcb.201703061
pmid: 28993467
51
Fischer B, Lüthy K, Paesmans J, De Koninck C, Maes I, Swerts J, Kuenen S, Uytterhoeven V, Verstreken P, Versées W (2016). Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. Nat Struct Mol Biol, 23(11): 965–973 https://doi.org/10.1038/nsmb.3297
pmid: 27669036
Fryer A E, Chalmers A, Connor J M, Fraser I, Povey S, Yates A D, Yates J R, Osborne J P (1987). Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet, 1(8534): 659–661 https://doi.org/10.1016/S0140-6736(87)90416-8
pmid: 2882085
Gai Z, Chu W, Deng W, Li W, Li H, He A, Nellist M, Wu G (2016a). Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region. J Mol Cell Biol: mjw001 doi:10.1093/jmcb/mjw001
pmid: 26798146
56
Gai Z, Wang Q, Yang C, Wang L, Deng W, Wu G (2016b). Structural mechanism for the arginine sensing and regulation of CASTOR1 in the mTORC1 signaling pathway. Cell Discov, 2(1): 16051 https://doi.org/10.1038/celldisc.2016.51
pmid: 28066558
57
Gao M, Kaiser C A (2006). A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast. Nat Cell Biol, 8(7): 657–667 https://doi.org/10.1038/ncb1419
pmid: 16732272
58
Gao X, Pan D (2001). TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev, 15(11): 1383–1392 https://doi.org/10.1101/gad.901101
pmid: 11390358
59
Garami A, Zwartkruis F J T, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma S C, Hafen E, Bos J L, Thomas G (2003). Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell, 11(6): 1457–1466 https://doi.org/10.1016/S1097-2765(03)00220-X
pmid: 12820960
60
Garcia-Saez I, Lacroix F B, Blot D, Gabel F, Skoufias D A (2011). Structural characterization of HBXIP: the protein that interacts with the anti-apoptotic protein survivin and the oncogenic viral protein HBx. J Mol Biol, 405(2): 331–340 https://doi.org/10.1016/j.jmb.2010.10.046
pmid: 21059355
61
Gong R, Li L, Liu Y, Wang P, Yang H, Wang L, Cheng J, Guan K L, Xu Y (2011). Crystal structure of the Gtr1p-Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation. Genes Dev, 25(16): 1668–1673 https://doi.org/10.1101/gad.16968011
pmid: 21816923
62
Grabacka M, Pierzchalska M, Dean M, Reiss K (2016). Regulation of ketone body metabolism and the role of ppara. Int J Mol Sci, 17(12): E2093 https://doi.org/10.3390/ijms17122093
pmid: 27983603
63
Groenewoud M J, Zwartkruis F J T (2013). Rheb and Rags come together at the lysosome to activate mTORC1. Biochem Soc Trans, 41(4): 951–955 https://doi.org/10.1042/BST20130037
pmid: 23863162
64
Gu X, Orozco J M, Saxton R A, Condon K J, Liu G Y, Krawczyk P A, Scaria S M, Harper J W, Gygi S P, Sabatini D M (2017). SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science, 358(6364): 813–818 https://doi.org/10.1126/science.aao3265
pmid: 29123071
65
Hanker A B, Mitin N, Wilder R S, Henske E P, Tamanoi F, Cox A D, Der C J (2010). Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling. Oncogene, 29(3): 380–391 https://doi.org/10.1038/onc.2009.336
pmid: 19838215
66
Hara K, Yonezawa K, Weng Q P, Kozlowski M T, Belham C, Avruch J (1998). Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem, 273(23): 14484–14494 https://doi.org/10.1074/jbc.273.23.14484
pmid: 9603962
67
Hashimoto Y, Shirane M, Nakayama K I (2018). TMEM55B contributes to lysosomal homeostasis and amino acid-induced mTORC1 activation. Genes Cells, https://doi.org/10.1111/gtc.12583
pmid: 29644770
68
Hasumi H, Baba M, Hong S B, Hasumi Y, Huang Y, Yao M, Valera V A, Linehan W M, Schmidt L S (2008). Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene, 415(1-2): 60–67 https://doi.org/10.1016/j.gene.2008.02.022
pmid: 18403135
Heitman J, Movva N R, Hall M N (1991). Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science, 253(5022): 905–909 https://doi.org/10.1126/science.1715094
pmid: 1715094
71
Helliwell S B, Wagner P, Kunz J, Deuter-Reinhard M, Henriquez R, Hall M N (1994). TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol Biol Cell, 5(1): 105–118 https://doi.org/10.1091/mbc.5.1.105
pmid: 8186460
72
Hoogeveen-Westerveld M, Exalto C, Maat-Kievit A, van den Ouweland A, Halley D, Nellist M (2010). Analysis of TSC1 truncations defines regions involved in TSC1 stability, aggregation and interaction. Biochim Biophys Acta, 1802(9): 774–781 https://doi.org/10.1016/j.bbadis.2010.06.004
pmid: 20547222
73
Hoogeveen-Westerveld M, van Unen L, van den Ouweland A, Halley D, Hoogeveen A, Nellist M (2012). The TSC1-TSC2 complex consists of multiple TSC1 and TSC2 subunits. BMC Biochem, 13(1): 18 https://doi.org/10.1186/1471-2091-13-18
pmid: 23006675
Huang J, Manning B D (2008). The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J, 412(2): 179–190 https://doi.org/10.1042/BJ20080281
pmid: 18466115
76
Huang J, Manning B D (2009). A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans, 37(Pt 1): 217–222 https://doi.org/10.1042/BST0370217
pmid: 19143635
77
Huttlin E L, Ting L, Bruckner R J, Gebreab F, Gygi M P, Szpyt J, Tam S, Zarraga G, Colby G, Baltier K, Dong R, Guarani V, Vaites L P, Ordureau A, Rad R, Erickson B K, Wühr M, Chick J, Zhai B, Kolippakkam D, Mintseris J, Obar R A, Harris T, Artavanis-Tsakonas S, Sowa M E, De Camilli P, Paulo J A, Harper J W, Gygi S P (2015). The bioplex network: A systematic exploration of the human interactome. Cell, 162(2): 425–440 https://doi.org/10.1016/j.cell.2015.06.043
pmid: 26186194
78
Im E, von Lintig F C, Chen J, Zhuang S, Qui W, Chowdhury S, Worley P F, Boss G R, Pilz R B (2002). Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene, 21(41): 6356–6365 https://doi.org/10.1038/sj.onc.1205792
pmid: 12214276
79
Imseng S, Aylett C H, Maier T (2018). Architecture and activation of phosphatidylinositol 3-kinase related kinases. Curr Opin Struct Biol, 49: 177–189 https://doi.org/10.1016/j.sbi.2018.03.010
pmid: 29625383
80
Inoki K, Li Y, Xu T, Guan K L (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev, 17(15): 1829–1834 https://doi.org/10.1101/gad.1110003
pmid: 12869586
81
Inoki K, Li Y, Zhu T, Wu J, Guan K L (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol, 4(9): 648–657 https://doi.org/10.1038/ncb839
pmid: 12172553
82
Jeong J H, Lee K H, Kim Y M, Kim D H, Oh B H, Kim Y G (2012). Crystal structure of the Gtr1p(GTP)-Gtr2p(GDP) protein complex reveals large structural rearrangements triggered by GTP-to-GDP conversion. J Biol Chem, 287(35): 29648–29653 https://doi.org/10.1074/jbc.C112.384420
pmid: 22807443
83
Jia R, Guardia C M, Pu J, Chen Y, Bonifacino J S (2017). BORC coordinates encounter and fusion of lysosomes with autophagosomes. Autophagy, 13(10): 1648–1663 https://doi.org/10.1080/15548627.2017.1343768
pmid: 28825857
84
Jung J, Genau H M, Behrends C (2015). Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9. Mol Cell Biol, 35(14): 2479–2494 https://doi.org/10.1128/MCB.00125-15
pmid: 25963655
85
Kandt R S, Haines J L, Smith M, Northrup H, Gardner R J, Shor t M P, Dumars K, Roach E S, Steingold S, Wall S, Blanton S H, Flodman P, Kwiatkowski D J, Jewell A, Weber J L, Roses A D, Pericak-Vanc e M A (1992). Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat Genet, 2(1): 37–41 https://doi.org/10.1038/ng0992-37
pmid: 1303246
86
Kelley K, Knockenhauer K E, Kabachinski G, Schwartz T U (2015). Atomic structure of the Y complex of the nuclear pore. Nat Struct Mol Biol, 22(5): 425–431 https://doi.org/10.1038/nsmb.2998
pmid: 25822992
87
Kennedy B K, Lamming D W (2016). The mechanistic target of rapamycin: the grand conductor of metabolism and aging. Cell Metab, 23(6): 990–1003 https://doi.org/10.1016/j.cmet.2016.05.009
pmid: 27304501
88
Kim D H, Sarbassov D D, Ali S M, King J E, Latek R R, Erdjument-Bromage H, Tempst P, Sabatini D M (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110(2): 163–175 https://doi.org/10.1016/S0092-8674(02)00808-5
pmid: 12150925
89
Kim D H, Sarbassov D D, Ali S M, Latek R R, Guntur K V, Erdjument-Bromage H, Tempst P, Sabatini D M (2003). GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell, 11(4): 895–904 https://doi.org/10.1016/S1097-2765(03)00114-X
pmid: 12718876
90
Kim E, Goraksha-Hicks P, Li L, Neufeld T P, Guan K L (2008). Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol, 10(8): 935–945 https://doi.org/10.1038/ncb1753
pmid: 18604198
91
Kim H, An S, Ro S H, Teixeira F, Park G J, Kim C, Cho C S, Kim J S, Jakob U, Lee J H, Cho U S (2015). Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. Nat Commun, 6(1): 10025 https://doi.org/10.1038/ncomms10025
pmid: 26612684
92
Kim J S, Ro S H, Kim M, Park H W, Semple I A, Park H, Cho U S, Wang W, Guan K L, Karin M, Lee J H (2015). Sestrin2 inhibits mTORC1 through modulation of GATOR complexes. Sci Rep, 5(1): 9502 https://doi.org/10.1038/srep09502
pmid: 25819761
93
Kimball S R, Gordon B S, Moyer J E, Dennis M D, Jefferson L S (2016). Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell Signal, 28(8): 896–906 https://doi.org/10.1016/j.cellsig.2016.03.008
pmid: 27010498
94
Kiontke S, Langemeyer L, Kuhlee A, Schuback S, Raunser S, Ungermann C, Kümmel D (2017). Architecture and mechanism of the late endosomal Rab7-like Ypt7 guanine nucleotide exchange factor complex Mon1-Ccz1. Nat Commun, 8: 14034 https://doi.org/10.1038/ncomms14034
pmid: 28051187
95
Kogan K, Spear E D, Kaiser C A, Fass D (2010). Structural conservation of components in the amino acid sensing branch of the TOR pathway in yeast and mammals. J Mol Biol, 402(2): 388–398 https://doi.org/10.1016/j.jmb.2010.07.034
pmid: 20655927
96
Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva N R, Hall M N (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell, 73(3): 585–596 https://doi.org/10.1016/0092-8674(93)90144-F
pmid: 8387896
97
Kurzbauer R, Teis D, de Araujo M E G, Maurer-Stroh S, Eisenhaber F, Bourenkov G P, Bartunik H D, Hekman M, Rapp U R, Huber L A, Clausen T (2004). Crystal structure of the p14/MP1 scaffolding complex: how a twin couple attaches mitogen-activated protein kinase signaling to late endosomes. Proc Natl Acad Sci USA, 101(30): 10984–10989 https://doi.org/10.1073/pnas.0403435101
pmid: 15263099
98
Kwiatkowski D J (2003). Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer Biol Ther, 2(5): 471–476 https://doi.org/10.4161/cbt.2.5.446
pmid: 14614311
Lee C, Goldberg J (2010). Structure of coatomer cage proteins and the relationship among COPI, COPII, and clathrin vesicle coats. Cell, 142(1): 123–132 https://doi.org/10.1016/j.cell.2010.05.030
pmid: 20579721
101
Levine T P, Daniels R D, Wong L H, Gatta A T, Gerondopoulos A, Barr F A (2013). Discovery of new Longin and Roadblock domains that form platforms for small GTPases in Ragulator and TRAPP-II. Small GTPases, 4(2): 62–69 https://doi.org/10.4161/sgtp.24262
pmid: 23511850
102
Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo J L, Bonenfant D, Oppliger W, Jenoe P, Hall M N (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell, 10(3): 457–468 https://doi.org/10.1016/S1097-2765(02)00636-6
pmid: 12408816
Lunin V V, Munger C, Wagner J, Ye Z, Cygler M, Sacher M (2004). The structure of the MAPK scaffold, MP1, bound to its partner, p14. A complex with a critical role in endosomal map kinase signaling. J Biol Chem, 279(22): 23422–23430 https://doi.org/10.1074/jbc.M401648200
pmid: 15016825
105
Marshall C B, Ho J, Buerger C, Plevin M J, Li G Y, Li Z, Ikura M, Stambolic V (2009). Characterization of the intrinsic and TSC2-GAP-regulated GTPase activity of Rheb by real-time NMR. Sci Signal, 2(55): ra3 https://doi.org/10.1126/scisignal.2000029
pmid: 19176517
106
Mazhab-Jafari M T, Marshall C B, Ishiyama N, Ho J, Di Palma V, Stambolic V, Ikura M (2012). An autoinhibited noncanonical mechanism of GTP hydrolysis by Rheb maintains mTORC1 homeostasis. Structure, 20(9): 1528–1539 https://doi.org/10.1016/j.str.2012.06.013
pmid: 22819219
107
Mc Cormack A, Sharpe C, Gregersen N, Smith W, Hayes I, George A M, Love D R (2015). 12q14 Microdeletions: Additional Case Series with Confirmation of a Macrocephaly Region. Case Rep Genet, 2015: 192071 https://doi.org/10.1155/2015/192071
pmid: 26266063
108
Metzger M B, Hristova V A, Weissman A M (2012). HECT and RING finger families of E3 ubiquitin ligases at a glance. J Cell Sci, 125(Pt 3): 531–537 https://doi.org/10.1242/jcs.091777
pmid: 22389392
Mozaffari M, Hoogeveen-Westerveld M, Kwiatkowski D, Sampson J, Ekong R, Povey S, den Dunnen J T, van den Ouweland A, Halley D, Nellist M (2009). Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex. BMC Med Genet, 10(1): 88 https://doi.org/10.1186/1471-2350-10-88
pmid: 19747374
111
Mu Z, Wang L, Deng W, Wang J, Wu G (2017). Structural insight into the Ragulator complex which anchors mTORC1 to the lysosomal membrane. Cell Discov, 3: 17049 https://doi.org/10.1038/celldisc.2017.49
pmid: 29285400
112
Nada S, Hondo A, Kasai A, Koike M, Saito K, Uchiyama Y, Okada M (2009). The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. EMBO J, 28(5): 477–489 https://doi.org/10.1038/emboj.2008.308
pmid: 19177150
113
Nagy V, Hsia K C, Debler E W, Kampmann M, Davenport A M, Blobel G, Hoelz A (2009). Structure of a trimeric nucleoporin complex reveals alternate oligomerization states. P roc Natl Acad Sci USA, 106(42): 17693–17698 https://doi.org/10.1073/pnas.0909373106
pmid: 19805193
114
Nakashima N, Noguchi E, Nishimoto T (1999). Saccharomyces cerevisiae putative G protein, Gtr1p, which forms complexes with itself and a novel protein designated as Gtr2p, negatively regulates the Ran/Gsp1p G protein cycle through Gtr2p. Genetics, 152(3): 853–867
pmid: 10388807
115
Neklesa T K, Davis R W (2009). A genome-wide screen for regulators of TORC1 in response to amino acid starvation reveals a conserved Npr2/3 complex. PLoS Genet, 5(6): e1000515 https://doi.org/10.1371/journal.pgen.1000515
pmid: 19521502
116
Nellist M, Goedbloed M A, Halley D J J(2003). Regulation of tuberous sclerosis complex (TSC) function by 14–3-3 proteins. Biochem. Soc. Trans. 31, 587–591. doi:10.1042/
117
Nellist M, van Slegtenhorst M A, Goedbloed M, van den Ouweland A M, Halley D J, van der Sluijs P (1999). Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J Biol Chem, 274(50): 35647–35652 https://doi.org/10.1074/jbc.274.50.35647
pmid: 10585443
118
Nickerson M L, Warren M B, Toro J R, Matrosova V, Glenn G, Turner M L, Duray P, Merino M, Choyke P, Pavlovich C P, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman M I, Linehan W M, Zbar B, Schmidt L S (2002). Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell, 2(2): 157–164 https://doi.org/10.1016/S1535-6108(02)00104-6
pmid: 12204536
119
Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K (2003). The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem, 278(18): 15461–15464 https://doi.org/10.1074/jbc.C200665200
pmid: 12604610
120
Nookala R K, Langemeyer L, Pacitto A, Ochoa-Montaño B, Donaldson J C, Blaszczyk B K, Chirgadze D Y, Barr F A, Bazan J F, Blundell T L (2012). Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open Biol, 2(8): 120071 https://doi.org/10.1098/rsob.120071
pmid: 22977732
121
Norton L E, Layman D K (2006). Leucine regulates translation initiation of protein synthesis in skeletal muscle after exercise. J Nutr, 136(2): 533S–537S https://doi.org/10.1093/jn/136.2.533S
pmid: 16424142
122
Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, Kikkawa U, Yonezawa K (2007). The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J Biol Chem, 282(28): 20329–20339 https://doi.org/10.1074/jbc.M702636200
pmid: 17517883
123
Pacitto A, Ascher D B, Wong L H, Blaszczyk B K, Nookala R K, Zhang N, Dokudovskaya S, Levine T P, Blundell T L (2015). Lst4, the yeast Fnip1/2 orthologue, is a DENN-family protein. Open Biol, 5(12): 150174 https://doi.org/10.1098/rsob.150174
pmid: 26631379
124
Pajusalu S, Reimand T, Õunap K (2015). Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome. Am J Med Genet A, 167A(8): 1913–1915 https://doi.org/10.1002/ajmg.a.37105
pmid: 25847626
125
Panchaud N, Péli-Gulli M P, De Virgilio C (2013a). Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci Signal, 6(277): ra42 https://doi.org/10.1126/scisignal.2004112
pmid: 23716719
126
Panchaud N, Péli-Gulli M P, De Virgilio C (2013b). SEACing the GAP that nEGOCiates TORC1 activation: evolutionary conservation of Rag GTPase regulation. Cell Cycle, 12(18): 2948–2952 https://doi.org/10.4161/cc.26000
pmid: 23974112
127
Park S Y, Jin W, Woo J R, Shoelson S E (2011). Crystal structures of human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating protein (RabGAP) domains reveal critical elements for GLUT4 translocation. J Biol Chem, 286(20): 18130–18138 https://doi.org/10.1074/jbc.M110.217323
pmid: 21454505
128
Parmar N, Tamanoi F ( 2010). Rheb G-Proteins and the Activation of mTORC1, in: The Enzymes. Elsevier, pp. 39–56. doi:10.1016/S1874-6047(10)27003-8
129
Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim Y C, Akopiants K, Guan K L, Karin M, Budanov A V (2014). Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Reports, 9(4): 1281–1291 https://doi.org/10.1016/j.celrep.2014.10.019
pmid: 25457612
130
Peeters H, Debeer P, Bairoch A, Wilquet V, Huysmans C, Parthoens E, Fryns J P, Gewillig M, Nakamura Y, Niikawa N, Van de Ven W, Devriendt K (2003). PA26 is a candidate gene for heterotaxia in humans: identification of a novel PA26-related gene family in human and mouse. Hum Genet, 112(5-6): 573–580 https://doi.org/10.1007/s00439-003-0917-5
pmid: 12607115
131
Péli-Gulli M P, Raucci S, Hu Z, Dengjel J, De Virgilio C (2017). Feedback Inhibition of the Rag GTPase GAP Complex Lst4-Lst7 Safeguards TORC1 from Hyperactivation by Amino Acid Signals. Cell Reports, 20(2): 281–288 https://doi.org/10.1016/j.celrep.2017.06.058
pmid: 28700931
132
Péli-Gulli M P, Sardu A, Panchaud N, Raucci S, De Virgilio C (2015). Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2. Cell Reports, 13(1): 1–7 https://doi.org/10.1016/j.celrep.2015.08.059
pmid: 26387955
133
Peng M, Yin N, Li M O (2014). Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell, 159(1): 122–133 https://doi.org/10.1016/j.cell.2014.08.038
pmid: 25259925
Peterson T R, Laplante M, Thoreen C C, Sancak Y, Kang S A, Kuehl W M, Gray N S, Sabatini D M (2009). DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 137(5): 873–886 https://doi.org/10.1016/j.cell.2009.03.046
pmid: 19446321
136
Petit C S, Roczniak-Ferguson A, Ferguson S M (2013). Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol, 202(7): 1107–1122 https://doi.org/10.1083/jcb.201307084
pmid: 24081491
137
Potter C J, Huang H, Xu T (2001). Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell, 105(3): 357–368 https://doi.org/10.1016/S0092-8674(01)00333-6
pmid: 11348592
138
Powis K, Zhang T, Panchaud N, Wang R, De Virgilio C, Ding J (2015). Crystal structure of the Ego1-Ego2-Ego3 complex and its role in promoting Rag GTPase-dependent TORC1 signaling. Cell Res, 25(9): 1043–1059 https://doi.org/10.1038/cr.2015.86
pmid: 26206314
139
Pu J, Keren-Kaplan T, Bonifacino J S (2017). A Ragulator-BORC interaction controls lysosome positioning in response to amino acid availability. J Cell Biol, 216(12): 4183–4197 https://doi.org/10.1083/jcb.201703094
pmid: 28993468
140
Pu J, Schindler C, Jia R, Jarnik M, Backlund P, Bonifacino J S (2015). BORC, a multisubunit complex that regulates lysosome positioning. Dev Cell, 33(2): 176–188 https://doi.org/10.1016/j.devcel.2015.02.011
pmid: 25898167
141
Qian C, Zhang Q, Wang X, Zeng L, Farooq A, Zhou M M (2005). Structure of the adaptor protein p14 reveals a profilin-like fold with distinct function. J Mol Biol, 347(2): 309–321 https://doi.org/10.1016/j.jmb.2005.01.031
pmid: 15740743
142
Qin J, Wang Z, Hoogeveen-Westerveld M, Shen G, Gong W, Nellist M, Xu W (2016). Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7). J Biol Chem, 291(16): 8591–8601 https://doi.org/10.1074/jbc.M115.701870
pmid: 26893383
143
Rebsamen M, Pochini L, Stasyk T, de Araújo M E G, Galluccio M, Kandasamy R K, Snijder B, Fauster A, Rudashevskaya E L, Bruckner M, Scorzoni S, Filipek P A, Huber K V M, Bigenzahn J W, Heinz L X, Kraft C, Bennett K L, Indiveri C, Huber L A, Superti-Furga G (2015). SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature, 519(7544): 477–481 https://doi.org/10.1038/nature14107
pmid: 25561175
144
Ricos M G, Hodgson B L, Pippucci T, Saidin A, Ong Y S, Heron S E, Licchetta L, Bisulli F, Bayly M A, Hughes J, Baldassari S, Palombo F, Santucci M, Meletti S, Berkovic S F, Rubboli G, Thomas P Q, Scheffer I E, Tinuper P, Geoghegan J, Schreiber A W, Dibbens L M, and the Epilepsy Electroclinical Study Group (2016). Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol, 79(1): 120–131 https://doi.org/10.1002/ana.24547
pmid: 26505888
145
Roberg K J, Bickel S, Rowley N, Kaiser C A (1997). Control of amino acid permease sorting in the late secretory pathway of Saccharomyces cerevisiae by SEC13, LST4, LST7 and LST8. Genetics, 147(4): 1569–1584
pmid: 9409822
146
Rosset C, Netto C B O, Ashton-Prolla P (2017). TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review. Genet Mol Biol, 40(1): 69–79 https://doi.org/10.1590/1678-4685-gmb-2015-0321
pmid: 28222202
147
Sabatini D M, Erdjument-Bromage H, Lui M, Tempst P, Snyder S H (1994). RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell, 78(1): 35–43 https://doi.org/10.1016/0092-8674(94)90570-3
pmid: 7518356
148
Sabers C J, Martin M M, Brunn G J, Williams J M, Dumont F J, Wiederrecht G, Abraham R T (1995). Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem, 270(2): 815–822 https://doi.org/10.1074/jbc.270.2.815
pmid: 7822316
149
Saito K, Araki Y, Kontani K, Nishina H, Katada T (2005). Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J Biochem, 137(3): 423–430 https://doi.org/10.1093/jb/mvi046
pmid: 15809346
150
Sancak Y, Bar-Peled L, Zoncu R, Markhard A L, Nada S, Sabatini D M (2010). Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell, 141(2): 290–303 https://doi.org/10.1016/j.cell.2010.02.024
pmid: 20381137
151
Sancak Y, Peterson T R, Shaul Y D, Lindquist R A, Thoreen C C, Bar-Peled L, Sabatini D M (2008). The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science, 320(5882): 1496–1501 https://doi.org/10.1126/science.1157535
pmid: 18497260
152
Sancak Y, Thoreen C C, Peterson T R, Lindquist R A, Kang S A, Spooner E, Carr S A, Sabatin D M (2007). PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell, 25(6): 903–915 https://doi.org/10.1016/j.molcel.2007.03.003
pmid: 17386266
153
Sato T, Nakashima A, Guo L, Tamanoi F (2009). Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem, 284(19): 12783–12791 https://doi.org/10.1074/jbc.M809207200
pmid: 19299511
154
Saucedo L J, Gao X, Chiarelli D A, Li L, Pan D, Edgar B A (2003). Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol, 5(6): 566–571 https://doi.org/10.1038/ncb996
pmid: 12766776
155
Saxton R A, Chantranupong L, Knockenhauer K E, Schwartz T U, Sabatini D M (2016a). Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature, 536(7615): 229–233 https://doi.org/10.1038/nature19079
pmid: 27487210
156
Saxton R A, Knockenhauer K E, Wolfson R L, Chantranupong L, Pacold M E, Wang T, Schwartz T U, Sabatini D M (2016b). Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science, 351(6268): 53–58 https://doi.org/10.1126/science.aad2087
pmid: 26586190
Schalm S S, Fingar D C, Sabatini D M, Blenis J (2003). TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol, 13(10): 797–806 https://doi.org/10.1016/S0960-9822(03)00329-4
pmid: 12747827
Schmitzberger F, Harrison S C (2012). RWD domain: a recurring module in kinetochore architecture shown by a Ctf19-Mcm21 complex structure. EMBO Rep, 13(3): 216–222 https://doi.org/10.1038/embor.2012.1
pmid: 22322944
161
Schürmann A, Brauers A, Massmann S, Becker W, Joost H G (1995). Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases. J Biol Chem, 270(48): 28982–28988 https://doi.org/10.1074/jbc.270.48.28982
pmid: 7499430
162
Scrima A, Thomas C, Deaconescu D, Wittinghofer A (2008). The Rap-RapGAP complex: GTP hydrolysis without catalytic glutamine and arginine residues. EMBO J, 27(7): 1145–1153 https://doi.org/10.1038/emboj.2008.30
pmid: 18309292
163
Sekiguchi T, Hirose E, Nakashima N, Ii M, Nishimoto T (2001). Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem, 276(10): 7246–7257 https://doi.org/10.1074/jbc.M004389200
pmid: 11073942
164
Shen K, Choe A, Sabatini D M (2017). Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability. Mol Cell, 68(3): 552–565.e8 https://doi.org/10.1016/j.molcel.2017.09.026
pmid: 29056322
165
Shen K, Huang R K, Brignole E J, Condon K J, Valenstein M L, Chantranupong L, Bomaliyamu A, Choe A, Hong C, Yu Z, Sabatini D M (2018). Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature, 556(7699): 64–69 https://doi.org/10.1038/nature26158
pmid: 29590090
166
Shumway S D, Li Y, Xiong Y (2003). 14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin. J Biol Chem, 278(4): 2089–2092 https://doi.org/10.1074/jbc.C200499200
pmid: 12468542
167
Springe r T A (1997). Folding of the N-terminal, ligand-binding region of integrin alpha-subunits into a beta-propeller domain. Proc Natl Acad Sci USA, 94(1): 65–72 https://doi.org/10.1073/pnas.94.1.65
pmid: 8990162
168
Starling G P, Yip Y Y, Sanger A, Morton P E, Eden E R, Dodding M P (2016). Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes. EMBO Rep, 17(6): 823–841 https://doi.org/10.15252/embr.201541382
pmid: 27113757
169
Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Breuer S, Thomas G, Hafen E (2003). Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol, 5(6): 559–565 https://doi.org/10.1038/ncb995
pmid: 12766775
170
Stuwe T, Correia A R, Lin D H, Paduc h M, Lu V T, Kossiakoff A A, Hoelz A (2015). Nuclear pores. Architecture of the nuclear pore complex coat. Science, 347(6226): 1148–1152 https://doi.org/10.1126/science.aaa4136
pmid: 25745173
171
Su M Y, Morris K L, Kim D J, Fu Y, Lawrence R, Stjepanovic G, Zoncu R, Hurley J H (2017). Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex. Mol Cell, 68(5): 835–846.e3 https://doi.org/10.1016/j.molcel.2017.10.016
pmid: 29107538
172
Sun W, Zhu Y J, Wang Z, Zhong Q, Gao F, Lou J, Gong W, Xu W (2013). Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations. Nat Commun, 4(1): 2135 https://doi.org/10.1038/ncomms3135
pmid: 23857276
173
Takahashi K, Nakagawa M, Young S G, Yamanaka S (2005). Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. J Biol Chem, 280(38): 32768–32774 https://doi.org/10.1074/jbc.M506280200
pmid: 16046393
174
Tapon N, Ito N, Dickson B J, Treisman J E, Hariharan I K (2001). The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell, 105(3): 345–355 https://doi.org/10.1016/S0092-8674(01)00332-4
pmid: 11348591
175
Tee A R, Fingar D C, Manning B D, Kwiatkowski D J, Cantley L C, Blenis J (2002). Tuberous sclerosis complex-1 and-2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA, 99(21): 13571–13576 https://doi.org/10.1073/pnas.202476899
pmid: 12271141
176
Tee A R, Manning B D, Roux P P, Cantley L C, Blenis J (2003). Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol, 13(15): 1259–1268 https://doi.org/10.1016/S0960-9822(03)00506-2
pmid: 12906785
177
Teis D, Wunderlich W, Huber L A (2002). Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. Dev Cell, 3(6): 803–814 https://doi.org/10.1016/S1534-5807(02)00364-7
pmid: 12479806
178
Tomasoni R, Mondino A (2011). The tuberous sclerosis complex: balancing proliferation and survival. Biochem Soc Trans, 39(2): 466–471 https://doi.org/10.1042/BST0390466
pmid: 21428921
179
Tsun Z Y, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, Sabatini D M (2013). The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell, 52(4): 495–505 https://doi.org/10.1016/j.molcel.2013.09.016
pmid: 24095279
180
van der Kant R, Jonker C T H, Wijdeven R H, Bakker J, Janssen L, Klumperman J, Neefjes J (2015). Characterization of the mammalian CORVET and HOPS complexes and their modular restructuring for endosome specificity. J Biol Chem, 290(51): 30280–30290 https://doi.org/10.1074/jbc.M115.688440
pmid: 26463206
181
van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell R G, Cheadle J P, Jones A C, Tachataki M, Ravine D, Sampson J R, Reeve M P, Richardson P, Wilmer F, Munro C, Hawkins T L, Sepp T, Ali J B, Ward S, Green A J, Yates J R, Kwiatkowska J, Henske E P, Short M P, Haines J H, Jozwiak S, Kwiatkowski D J (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science, 277(5327): 805–808 https://doi.org/10.1126/science.277.5327.805
pmid: 9242607
182
van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P (1998). Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet, 7(6): 1053–1057 https://doi.org/10.1093/hmg/7.6.1053
pmid: 9580671
183
Vander Haar E, Lee S I, Bandhakavi S, Griffin T J, Kim D H (2007). Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol, 9(3): 316–323 https://doi.org/10.1038/ncb1547
pmid: 17277771
184
Velasco-Miguel S, Buckbinder L, Jean P, Gelbert L, Talbott R, Laidlaw J, Seizinger B, Kley N (1999). PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene, 18(1): 127–137 https://doi.org/10.1038/sj.onc.1202274
pmid: 9926927
185
Vilella-Bach M, Nuzzi P, Fang Y, Chen J (1999). The FKBP12-rapamycin-binding domain is required for FKBP12-rapamycin-associated protein kinase activity and G1 progression. J Biol Chem, 274(7): 4266–4272 https://doi.org/10.1074/jbc.274.7.4266
pmid: 9933627
186
Wang S, Tsun Z Y, Wolfson R L, Shen K, Wyant G A, Plovanich M E, Yuan E D, Jones T D, Chantranupong L, Comb W, Wang T, Bar-Peled L, Zoncu R, Straub C, Kim C, Park J, Sabatini B L, Sabatini D M (2015). Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science, 347(6218): 188–194 https://doi.org/10.1126/science.1257132
pmid: 25567906
187
Wenter R, Hütz K, Dibbern D, Li T, Reisinger V, Plösche r M, Eichacker L, Eddie B, Hanson T, Bryant D A, Overmann J (2010). Expression-based identification of genetic determinants of the bacterial symbiosis ‘Chlorochromatium aggregatum’. Environ Microbiol, 12(8): 2259–2276 doi:10.1111/j.1462-2920.2010.02206.x
pmid: 21966918
188
Whittaker C A, Hynes R O (2002). Distribution and evolution of von Willebrand/integrin A domains: widely dispersed domains with roles in cell adhesion and elsewhere. Mol Biol Cell, 13(10): 3369–3387 https://doi.org/10.1091/mbc.e02-05-0259
pmid: 12388743
189
Whittle J R R, Schwartz T U (2010). Structure of the Sec13-Sec16 edge element, a template for assembly of the COPII vesicle coat. J Cell Biol, 190(3): 347–361 https://doi.org/10.1083/jcb.201003092
pmid: 20696705
190
Wolfson R L, Chantranupong L, Wyant G A, Gu X, Orozco J M, Shen K, Condon K J, Petri S, Kedir J, Scaria S M, Abu-Remaileh M, Frankel W N, Sabatini D M (2017). KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature, 543(7645): 438–442 https://doi.org/10.1038/nature21423
pmid: 28199306
Wu X, Tu B P (2011). Selective regulation of autophagy by the Iml1-Npr2-Npr3 complex in the absence of nitrogen starvation. Mol Biol Cell, 22(21): 4124–4133 https://doi.org/10.1091/mbc.e11-06-0525
pmid: 21900499
193
Xia J, Wang R, Zhang T, Ding J (2016). Structural insight into the arginine-binding specificity of CASTOR1 in amino acid-dependent mTORC1 signaling. Cell Discov, 2(1): 16035 https://doi.org/10.1038/celldisc.2016.35
pmid: 27648300
194
Xiong J P, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott D L, Joachimiak A, Goodman S L, Arnaout M A (2001). Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science, 294(5541): 339–345 https://doi.org/10.1126/science.1064535
pmid: 11546839
Yamagata K, Sanders L K, Kaufmann W E, Yee W, Barnes C A, Nathans D, Worley P F (1994). rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J Biol Chem, 269(23): 16333–16339
pmid: 8206940
197
Yang H, Wang J, L M, Chen X, Huang M, Tan D, Dong M Q, Wong C C L, Wang J, Xu Y, Wang H W (2016). 4.4 Å Resolution Cryo-EM structure of human mTOR Complex 1. Protein Cell 7, 878–887. https://doi.org/10.1007/s13238-016-0346-6
198
Yang H, Jiang X, Li B, Yang H J, Miller M, Yang A, Dhar A, Pavletich N P (2017). Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature, 552(7685): 368–373 https://doi.org/10.1038/nature25023
pmid: 29236692
199
Yang H, Rudge D G, Koos J D, Vaidialingam B, Yang H J, Pavletich N P (2013). mTOR kinase structure, mechanism and regulation. Nature, 497(7448): 217–223 https://doi.org/10.1038/nature12122
pmid: 23636326
200
Yonehara R, Nada S, Nakai T, Nakai M, Kitamura A, Ogawa A, Nakatsumi H, Nakayama K I, Li S, Standley D M, Yamashita E, Nakagawa A, Okada M (2017). Structural basis for the assembly of the Ragulator-Rag GTPase complex. Nat Commun, 8(1): 1625 https://doi.org/10.1038/s41467-017-01762-3
pmid: 29158492
201
Yu Y, Li S, Xu X, Li Y, Guan K, Arnold E, Ding J (2005). Structural basis for the unique biological function of small GTPase RHEB. J Biol Chem, 280(17): 17093–17100 https://doi.org/10.1074/jbc.M501253200
pmid: 15728574
202
Zanetti G, Prinz S, Daum S, Meister A, Schekman R, Bacia K, Briggs J A G (2013). The structure of the COPII transport-vesicle coat assembled on membranes. eLife, 2: e00951 https://doi.org/10.7554/eLife.00951
pmid: 24062940
203
Zech R, Kiontke S, Mueller U, Oeckinghaus A, Kümmel D (2016). Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis. J Biol Chem, 291(38): 20008–20020 https://doi.org/10.1074/jbc.M116.732446
pmid: 27493206
204
Zhang D, Iyer L M, He F, Aravind L (2012). Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease. Front Genet, 3: 283 https://doi.org/10.3389/fgene.2012.00283
pmid: 23248642
205
Zhang T, Péli-Gulli M P, Yang H, De Virgilio C, Ding J (2012). Ego3 functions as a homodimer to mediate the interaction between Gtr1-Gtr2 and Ego1 in the ego complex to activate TORC1. Structure, 20(12): 2151–2160 https://doi.org/10.1016/j.str.2012.09.019
pmid: 23123112
206
Zhang T, Wang R, Wang Z, Wang X, Wang F, Ding J (2017). Structural basis for Ragulator functioning as a scaffold in membrane-anchoring of Rag GTPases and mTORC1. Nat Commun, 8(1): 1394 https://doi.org/10.1038/s41467-017-01567-4
pmid: 29123114
207
Zhang Y, Gao X, Saucedo L J, Ru B, Edgar B A, Pan D (2003). Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol, 5(6): 578–581 https://doi.org/10.1038/ncb999
pmid: 12771962
208
Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini D M (2011). mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science, 334(6056): 678–683 https://doi.org/10.1126/science.1207056
pmid: 22053050
