Please wait a minute...

Frontiers in Biology

Front. Biol.    2018, Vol. 13 Issue (4) : 237-262
Signal integration in the (m)TORC1 growth pathway
Kailash Ramlaul, Christopher H. S. Aylett()
Section of Structural Biology, Department of Medicine, Imperial College London, SW7 2AZ, UK
Download: PDF(1246 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

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.

Keywords mTORC1      nutrient sensing      GATOR complex      TSC complex      Rag GTPases      Rheb     
Corresponding Author(s): Christopher H. S. Aylett   
Online First Date: 26 July 2018    Issue Date: 10 September 2018
 Cite this article:   
Kailash Ramlaul,Christopher H. S. Aylett. Signal integration in the (m)TORC1 growth pathway[J]. Front. Biol., 2018, 13(4): 237-262.
E-mail this article
E-mail Alert
Articles by authors
Kailash Ramlaul
Christopher H. S. Aylett
Fig.1  Schematic of mTORC1 regulation in response to multiple stimuli. In the absence of the appropriate signals, mTORC1 is not localized to the lysosome by RagA/B-RagC/D and therefore not allosterically activated by Rheb. Inhibitory GAPs for the RagA/B and Rheb GTPases – GATOR1 and TSCC, respectively – act on their targets, while FLCN-FNIP activates RagC/D. In the presence of amino acids and key metabolites, SESN2 and CASTOR1 dissociate from GATOR2, enabling it to inhibit GATOR1 through an as-yet incompletely described mechanism, while SAMTOR dissociates from GATOR1-KICSTOR and may enable recognition of GATOR1 by GATOR2. In the absence of external stresses, such as DNA damage, low cellular energy status and reactive oxygen species production, as well as positive growth factor signaling, TSCC-mediated Rheb inhibition is relieved by posttranslational modifications of the integrator complex, which likely lead to dispersion of TSCC from the lysosome surface. Both the Rag heterodimer and Rheb GTPases can now cooperatively activate mTORC1 to stimulate biogenesis.
Fig.2  Structural biology of the nutrient sensors SESN2, CASTOR1, and SAMTOR. A. Domain organization of SESN2 and CASTOR1 and predicted domain organization of SAMTOR. Black and gray outlines represent structurally resolved or predicted regions, respectively, while colored and gray bars reflect specific features with known or putative functions, respectively. B. Crystal structure of leucine-bound SESN2 (PDB ID: 5DJ4), with bound leucine shown as cyan in stick representation. Leucine- and GATOR2-interacting residues are shown in teal and purple respectively, as highlighted in A. C. Leucine binding pocket of SESN2, as inset in B. Polar contacts are indicated by blue dashed lines, and hydrophobic interactions by yellow. D. Crystal structures of the arginine-bound, and apo, CASTOR1 homodimer (Arg-bound PDB ID: 5I2C; apo: 5GT8), with bound arginine shown as light green in stick representation. Arginine- and GATOR2-interacting residues are shown in green and purple respectively, as shown in A. E. Arginine binding pocket of CASTOR1, as inset in D. Polar contacts are indicated by bright green dashed lines. The loop which closes over the CASTOR1 binding pocket has been omitted for clarity between residues 269-276, indicated by maroon diamonds. F. Comparison of ACT4 residues 270-280 between the arginine-bound and apo CASTOR1, which form a loop over the bound arginine. Residues 275-279 are unobserved in the apo CASTOR1 crystal structure, indicating disorder.
Fig.3  Structural biology of the GATOR1 complex. (A) Domain organization of DEPDC5, NPRL2 and NPRL3. The dark red bar indicates the region of the DEPDC5 SHEN domain which interacts with RagA. (B) Cryo-electron microscopy structure of the mammalian GATOR1-RagA-RagC complex (PDB ID: 6CES; EMDB: EMD-7464). (C) Focused view of the DEPDC5SHEN-RagAGTPase domain interaction, highlighting the end-to-end β-strand interaction of the two domains and its proximity to the RagAGTPase nucleotide binding pocket. The RagA P loop, switch I and II regions are colored pale green. Bound GTP is shown as light green in stick representation.
Fig.4  Structural biology of the small GTPases Rag and the Ragulator complex. (A) Domain organization of the Rag GTPases and Ragulator complex components LAMTOR1-5. Pale green lines under RagA indicate, from N- to C terminus, the P-loop (residues 14-21), switch I (residues 39-45) and switch II (residues 60-67) regions. Pink lines under RagC similarly indicate the P-loop (residues 68-75), switch I (residues 91-99) and switch II (residues 114-122) regions. The brown bar at the LAMTOR1 N terminus indicates the palmitoylation and myristoylation motifs, while colored bars reflect the regions of interaction with other Ragulator-Rag components, colored according to the interacting proteins. (B) Crystal structure of Ragulator in complex with the Rag GTPase roadblock domain heterodimer (PDB ID: 6EHP). (C) Structure of the Rag GTPase heterodimer from the cryo-EM structure of the GATOR1-Rag GTPase complex (PDB ID: 6CES; EMDB: EMD-7464). RagA-bound GTP is shown as light green in stick representation. The P loop, switch I and II regions of RagA and RagC are colored as highlighted in A. (D) Comparison of the crystal structures of Gtr1GMPPNP-Gtr2GMPPNP (PDB ID: 3R7W) and Gtr1GTP-Gtr2GDP (PDB ID: 4ARZ), highlighting the conformational change of the Gtr2 switch I region. E. Gtr1-Gtr2 GTPase domain interface, as inset in D. Gtr1 residues R36 and R37 make direct contacts with the neighboring Gtr2 nucleotide binding pocket and the bound GDP itself. Polar contacts are indicated by dark gray dashed lines.
Fig.5  Structural biology and predicted domains of TSCC. (A) Predicted domain organization of TSC1, TSC2 and TBC1D7. Black and black-dashed outlines indicate structurally resolved proteins or fragments, respectively, while gray outlines represent predicted regions. Grey bars reflect specific features with putative functions. The crimson bar in the TSC1 coiled-coil region denotes a TSC2 interaction site. Similarly, the light orange bar in the TSC2 α-solenoid denotes a TSC1-interacting region. The pink bar in TBC1D7 represents the TSC1-interacting helix. (B) Crystal structure of the S. pombe TSC1 core domain monomer, alongside the decamer observed in each crystal form (PDB ID: 4KK0). (C) Crystal structure of the C. thermophilum TSC2 N-terminal α-solenoid fragment (PDB ID: 5HIU). (D) Crystal structure of the deposited, but as-yet unpublished, TBC1D7 crystal structure (PDB ID: 3QWL). (E) Crystal structure of a TBC1D7-TSC1 coiled coil complex (PDB ID: 4Z6Y), indicating a dimer-of-dimers structure. (F) Crystal structure of TBC1D7-TSC1 coiled coil complex (PDB ID: 5EJC), indicating a helical-bundle architecture formed between dimerization of two TSC1 coiled coil fragments and one TBC1D7 molecule. (G) Superposition of the TBC1D7-TSC1 coiled coil complex structures, highlighting the similarity in binding conformation of the two different TSC1 coil fragments. TSC1-interacting residues are shown in pink, as highlighted in A, while TBC1D7-interacting residues are colored per complex.
Fig.6  Structural biology of the small GTPase Rheb and the Rheb-dependent activation of mTORC1. (A) Domain organization of Rheb. Olive green lines indicate, from N- to C terminus, the P-loop (residues 12-20), switch I (residues 33-41) and switch II (residues 63-79) regions. (B) Crystal structure of GTP-bound Rheb (PDB ID: 1XTS), with bound GTP shown as light green in stick representation. The P loop, switch I and II regions are shown in olive green, as highlighted in A. (C) Focused view of the nucleotide binding pocket, highlighting the conformational difference between key GTP binding residue Y35 between the GDP- and GTP-bound states. (D) Comparison of the cryo-EM structures of mTORC1 alone (top; PDB ID: 6BCX; EMDB: EMD-7087) and mTORC1-Rheb (bottom; PDB ID: EMD-7086). Major conformational movements which occur upon Rheb binding, such as the N-HEAT rotation and kinase N-lobe compaction, are indicated by arrows. The mTOR kinase active sites are shown as insets in each, with the Mg2+ -coordinating residues N2343 and D2357, and catalytic residue H2340, shown. Interatomic distances labeled in Å indicate that in Rheb-bound mTORC1 these key residues shift by<1 Å toward the bound ATP.
Fig.7  Wider regulation of eukaryotic cell metabolism by mTORC1. Besides the well-characterized regulation of protein synthesis and autophagy by mTORC1, mTOR also forms a plasma membrane-localized, functionally segregated and rapamycin-insensitive complex called mTORC2, which controls cytoskeletal organization pathways and coordinates cell survival with cellular metabolism. mTORC2 is also a key activator of protein kinase Akt, which inhibits TSCC and therefore activates mTORC1 through Rheb. On the lysosome, the Ragulator complex interacts with several lysosomally-localized proteins, including the v-ATPase, SLC38A9, NPC1 and BORC complex, coordinating wider metabolism and lysosomal biogenesis and positioning to mTORC1 signaling. Additionally, the FLCN-FNIP complex also regulates lysosome positioning through interaction with Rab-RILP complexes. The GATOR2 complex interchanges subunits with the NPC and COPII vesicle coat, and alongside KICSTOR, which also features similar architectures, may have roles in lysosome-endosome and/or lysosome-autophagosome tethering and fusion. As recently determined, GATOR1 exhibits two modes of interaction with RagA/B and this interplay may endow the Rag signaling axis with unique properties. Finally, the Rag and Rheb GTPases both feature GAPs, and there is evidence supporting the role of Ragulator as a RagA/B GEF, however GEFs have not been conclusively identified for RagC/D or Rheb. The Rheb-GEF may localize to the Golgi, which is postulated to be the site of Rheb activation.
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 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 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 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 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 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 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 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 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 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 pmid: 23932106
11 Baulac S (2016). mTOR signaling pathway genes in focal epilepsies. Prog Brain Res, 226: 61–79 pmid: 27323939
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 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 pmid: 7836465
14 Bosotti R, Isacchi A, Sonnhammer E L (2000). FAT: a novel domain in PIK-related kinases. Trends Biochem Sci, 25(5): 225–227 pmid: 10782091
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 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 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 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 pmid: 15545625
19 Budanov A V, Karin M (2008). p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell, 134(3): 451–460 pmid: 18692468
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 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 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 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 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 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 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 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 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 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 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 pmid: 7539137
31 Cherfils J (2017). Encoding Allostery in mTOR Signaling: The Structure of the Rag GTPase/Ragulator Complex. Mol Cell, 68(5): 823–824 pmid: 29220648
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 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 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 pmid: 18479705
35 Daste F, Galli T, Tareste D (2015). Structure and function of longin SNAREs. J Cell Sci, 128(23): 4263–4272 pmid: 26567219
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 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 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 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 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 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 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 pmid: 22795129
43 Dodding M P (2017). Folliculin- A tumor suppressor at the intersection of metabolic signaling and membrane traffic. Small GTPases, 8(2): 100–105 pmid: 27355777
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 pmid: 15989961
46 Durán R V, Hall M N (2012). Regulation of TOR by small GTPases. EMBO Rep, 13(2): 121–128 pmid: 22240970
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 pmid: 23414967
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 pmid: 17604721
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 pmid: 25816988
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 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 pmid: 27669036
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 pmid: 19624305
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 pmid: 2882085
54 Fukuda M (2011). TBC proteins: GAPs for mammalian small GTPase Rab? Biosci Rep, 31(3): 159–168 pmid: 21250943
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
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 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 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 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 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 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 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 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 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 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 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 pmid: 9603962
67 Hashimoto Y, Shirane M, Nakayama K I (2018). TMEM55B contributes to lysosomal homeostasis and amino acid-induced mTORC1 activation. Genes Cells, 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 pmid: 18403135
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 pmid: 24863881
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 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 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 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 pmid: 23006675
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 pmid: 18160040
75 Huang J, Manning B D (2008). The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J, 412(2): 179–190 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 pmid: 14614311
99 Laplante M, Sabatini D M (2012). mTOR signaling in growth control and disease. Cell, 149(2): 274–293 pmid: 22500797
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 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 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 pmid: 12408816
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 pmid: 15854902
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 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 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 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 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 pmid: 22389392
109 Morris S MJr (2006). Arginine: beyond protein. Am J Clin Nutr, 83(2): 508S–512S pmid: 16470022
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 pmid: 25259925
134 Peng M, Yin N, Li M O (2017). SZT2 dictates GATOR control of mTORC1 signalling. Nature, 543(7645): 433–437 pmid: 28199315
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 pmid: 26586190
157 Schalm S S, Blenis J (2002). Identification of a conserved motif required for mTOR signaling. Curr Biol, 12(8): 632–639 pmid: 11967149
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 pmid: 12747827
159 Schmidt L S, Linehan W M (2018). FLCN: The causative gene for Birt-Hogg-Dubé syndrome. Gene, 640: 28–42 pmid: 28970150
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 pmid: 12479806
178 Tomasoni R, Mondino A (2011). The tuberous sclerosis complex: balancing proliferation and survival. Biochem Soc Trans, 39(2): 466–471 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 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 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 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 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 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 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 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 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 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 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 pmid: 28199306
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 pmid: 28768171
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 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 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 pmid: 11546839
195 Xu C, Min J (2011). Structure and function of WD40 domain proteins. Protein Cell, 2(3): 202–214 pmid: 21468892
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
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.
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 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 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 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 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 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 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 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 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 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 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 pmid: 22053050
[1] FIB-10501-OF-CA_suppl_1 Download
Related articles from Frontiers Journals
[1] Felicia Tsang,Su-Ju Lin. Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD+ homeostasis and contributes to longevity[J]. Front. Biol., 2015, 10(4): 333-357.
[2] Catherine C. Y. CHANG, Jie SUN, Ta-Yuan CHANG. Membrane-bound O-acyltransferases (MBOAT)[J]. Front Biol, 2011, 6(3): 177-182.
Full text