Received date: 04 May 2018
Accepted date: 05 Jun 2018
Published date: 10 Sep 2018
Copyright
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.
Key words： mTORC1; nutrient sensing; GATOR complex; TSC complex; Rag GTPases; Rheb
Kailash Ramlaul , Christopher H. S. Aylett . Signal integration in the (m)TORC1 growth pathway[J]. Frontiers in Biology, 2018 , 13(4) : 237 -262 . DOI: 10.1007/s11515-018-1501-7
| 1 |
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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 11 |
Baulac S (2016). mTOR signaling pathway genes in focal epilepsies. Prog Brain Res, 226: 61–79
|
| 12 |
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
|
| 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
|
| 14 |
Bosotti R, Isacchi A, Sonnhammer E L (2000). FAT: a novel domain in PIK-related kinases. Trends Biochem Sci, 25(5): 225–227
|
| 15 |
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
|
| 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
|
| 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
|
| 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
|
| 19 |
Budanov A V, Karin M (2008). p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell, 134(3): 451–460
|
| 20 |
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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 31 |
Cherfils J (2017). Encoding Allostery in mTOR Signaling: The Structure of the Rag GTPase/Ragulator Complex. Mol Cell, 68(5): 823–824
|
| 32 |
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
|
| 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
|
| 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
|
| 35 |
Daste F, Galli T, Tareste D (2015). Structure and function of longin SNAREs. J Cell Sci, 128(23): 4263–4272
|
| 36 |
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
|
| 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
|
| 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
|
| 39 |
Demetriades C, Plescher M, Teleman A A (2016). Lysosomal recruitment of TSC2 is a universal response to cellular stress. Nat Commun, 7: 10662
|
| 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
|
| 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
|
| 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
|
| 43 |
Dodding M P (2017). Folliculin- A tumor suppressor at the intersection of metabolic signaling and membrane traffic. Small GTPases, 8(2): 100–105
|
| 44 |
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
|
| 46 |
Durán R V, Hall M N (2012). Regulation of TOR by small GTPases. EMBO Rep, 13(2): 121–128
|
| 47 |
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
|
| 48 |
Fath S, Mancias J D, Bi X, Goldberg J (2007). Structure and organization of coat proteins in the COPII cage. Cell, 129(7): 1325–1336
|
| 49 |
Fawal M A, Brandt M, Djouder N (2015). MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation. Dev Cell, 33(1): 67–81
|
| 50 |
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
|
| 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
|
| 52 |
Frankel W N, Yang Y, Mahaffey C L, Beyer B J, O’Brien T P (2009). Szt2, a novel gene for seizure threshold in mice. Genes Brain Behav, 8(5): 568–576
|
| 53 |
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
|
| 54 |
Fukuda M (2011). TBC proteins: GAPs for mammalian small GTPase Rab? Biosci Rep, 31(3): 159–168
|
| 55 |
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
|
| 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
|
| 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
|
| 58 |
Gao X, Pan D (2001). TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev, 15(11): 1383–1392
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 67 |
Hashimoto Y, Shirane M, Nakayama K I (2018). TMEM55B contributes to lysosomal homeostasis and amino acid-induced mTORC1 activation. Genes Cells,
|
| 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
|
| 69 |
Heard J J, Fong V, Bathaie S Z, Tamanoi F (2014). Recent progress in the study of the Rheb family GTPases. Cell Signal, 26(9): 1950–1957
|
| 70 |
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
|
| 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
|
| 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
|
| 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
|
| 74 |
Hsia K C, Stavropoulos P, Blobel G, Hoelz A (2007). Architecture of a coat for the nuclear pore membrane. Cell, 131(7): 1313–1326
|
| 75 |
Huang J, Manning B D (2008). The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J, 412(2): 179–190
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 99 |
Laplante M, Sabatini D M (2012). mTOR signaling in growth control and disease. Cell, 149(2): 274–293
|
| 100 |
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
|
| 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
|
| 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
|
| 103 |
Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005). Rheb binds and regulates the mTOR kinase. Curr Biol, 15(8): 702–713
|
| 104 |
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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 109 |
Morris S MJr (2006). Arginine: beyond protein. Am J Clin Nutr, 83(2): 508S–512S
|
| 110 |
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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 134 |
Peng M, Yin N, Li M O (2017). SZT2 dictates GATOR control of mTORC1 signalling. Nature, 543(7645): 433–437
|
| 135 |
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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 157 |
Schalm S S, Blenis J (2002). Identification of a conserved motif required for mTOR signaling. Curr Biol, 12(8): 632–639
|
| 158 |
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
|
| 159 |
Schmidt L S, Linehan W M (2018). FLCN: The causative gene for Birt-Hogg-Dubé syndrome. Gene, 640: 28–42
|
| 160 |
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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 178 |
Tomasoni R, Mondino A (2011). The tuberous sclerosis complex: balancing proliferation and survival. Biochem Soc Trans, 39(2): 466–471
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 191 |
Wolfson R L, Sabatini D M (2017). The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway. Cell Metab, 26(2): 301–309
|
| 192 |
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
|
| 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
|
| 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
|
| 195 |
Xu C, Min J (2011). Structure and function of WD40 domain proteins. Protein Cell, 2(3): 202–214
|
| 196 |
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
|
| 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.
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
| 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
|
/
| 〈 |
|
〉 |