Proton-assisted Amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes

PLoS ONE

Volumn 7, Issue 5, 2012, Pages

  Ögmundsdóttir, Margrét H ^a   Heublein, Sabine ^a   Kazi, Shubana ^a   Reynolds, Bruno ^a   Visvalingam, Shivanthy M ^a   Shaw, Michael K ^b   Goberdhan, Deborah C I ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; AMINO ACID TRANSPORTER; GREEN FLUORESCENT PROTEIN; GUANOSINE TRIPHOSPHATASE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; NUCLEIC ACID BINDING PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTON ASSISTED AMINO ACID TRANSPORTER 1; RAG PROTEIN; RHEB PROTEIN; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CELL GROWTH; CELL LEVEL; CELL SURFACE; CELL TYPE; COMPLEX FORMATION; CONTROLLED STUDY; DROSOPHILA; ENDOCYTOSIS; ENDOSOME; GENETIC ANALYSIS; HUMAN; HUMAN CELL; IMMUNOHISTOCHEMISTRY; IN VIVO STUDY; LYSOSOME; MAMMAL CELL; NONHUMAN; PROTEIN INTERACTION; PROTEIN LOCALIZATION; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; TRANSCRIPTION INITIATION;

AMINO ACID TRANSPORT SYSTEMS; AMINO ACIDS; ANIMALS; DROSOPHILA MELANOGASTER; ENDOCYTOSIS; ENDOSOMES; FEMALE; GTP PHOSPHOHYDROLASES; HEK293 CELLS; HUMANS; INTRACELLULAR MEMBRANES; LYSOSOMES; MONOMERIC GTP-BINDING PROTEINS; MULTIPROTEIN COMPLEXES; NEUROPEPTIDES; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN BINDING; PROTEINS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; SYMPORTERS; TOR SERINE-THREONINE KINASES;

MAMMALIA;

EID: 84871260456     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0036616     Document Type: Article

References (73)

1. Laplante M, Sabatini DM, (2009) mTOR signaling at a glance. J Cell Sci 122: 3589-3594.
2. Guertin DA, Sabatini DM, (2007) Defining the role of mTOR in cancer. Cancer Cell 12: 9-22.
3. Wellen KE, Thompson CB, (2010) Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell 40: 323-332.
4. Dann SG, Selvaraj A, Thomas G, (2007) mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 13: 252-259.
5. Woods SC, Seeley RJ, Cota D, (2008) Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr 28: 295-311.
6. Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC, (2009) Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 16: 46-56.
7. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, et al. (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460: 392-395.
8. Toivonen JM, Partridge L, (2009) Endocrine regulation of aging and reproduction in Drosophila. Mol Cell Endocrinol 299: 39-50.
9. Azim H, Azim HA Jr, Escudier B, (2010) Targeting mTOR in cancer: renal cell is just a beginning. Target Oncol 5: 269-280.
10. Garcia-Echeverria C, (2010) Allosteric and ATP-competitive kinase inhibitors of mTOR for cancer treatment. Bioorg Med Chem Lett 20: 4308-4312.
11. Yuan R, Kay A, Berg WJ, Lebwohl D, (2009) Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2: 45.
12. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159-168.
13. Huang J, Manning BD, (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37: 217-222.
14. Dancey J, (2010) mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 7: 209-219.
15. Sparks CA, Guertin DA, (2010) Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 29: 3733-3744.
16. Goberdhan DC, (2010) Intracellular amino acid sensing and mTORC1-regulated growth: new ways to block an old target? Curr Opin Investig Drugs 11: 1360-1367.
17. Goberdhan DC, Wilson C, (2003) PTEN: tumour suppressor, multifunctional growth regulator and more. Hum Mol Genet 12 Spec No 2: R239-248.
18. Vanhaesebroeck B, Vogt PK, Rommel C, (2010) PI3K: from the bench to the clinic and back. Curr Top Microbiol Immunol 347: 1-19.
19. Goberdhan DC, Wilson C, (2003) The functions of insulin signaling: size isn't everything, even in Drosophila. Differentiation 71: 375-397.
20. Hafen E, (2004) Cancer, type 2 diabetes, and ageing: news from flies and worms. Swiss Med Wkly 134: 711-719.
21. Goberdhan DC, Wilson C, (2002) Insulin receptor-mediated organ overgrowth in Drosophila is not restricted by body size. Dev Genes Evol 212: 196-202.
22. Hennig K, Colombani J, Neufeld T, (2006) TOR coordinates bulk and targeted endocytosis in the Drosophila melanogaster fat body to regulate cell growth. The Journal of Cell Biology 173: 963-974.
23. Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, et al. (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7: 561-573.
24. Kalaany NY, Sabatini DM, (2009) Tumours with PI3K activation are resistant to dietary restriction. Nature 458: 725-731.
25. Hsu PP, Sabatini DM, (2008) Cancer cell metabolism: Warburg and beyond. Cell 134: 703-707.
26. Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, et al. (2009) Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 296: E592-602.
27. Goberdhan DC, Ögmundsdóttir MH, Kazi S, Reynolds B, Visvalingam SM, et al. (2009) Amino acid sensing and mTOR regulation: inside or out? Biochem Soc Trans 37: 248-252.
28. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL, (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biology 10: 935-945.
29. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, et al. (2008) The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1. Science 320: 1496-1501.
30. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, et al. (2010) Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids. Cell 141: 290-303.
31. Binda M, Peli-Gulli MP, Bonfils G, Panchaud N, Urban J, et al. (2009) The Vam6 GEF controls TORC1 by activating the EGO complex. Mol Cell 35: 563-573.
32. Sturgill TW, Cohen A, Diefenbacher M, Trautwein M, Martin DE, et al. (2008) TOR1 and TOR2 have distinct locations in live cells. Eukaryot Cell 7: 1819-1830.
33. Cohen A, Hall MN, (2009) An amino acid shuffle activates mTORC1. Cell 136: 399-400.
34. Reynolds B, Laynes R, Ögmundsdóttir MH, Boyd CAR, Goberdhan DCI, (2007) Amino acid transporters and nutrient-sensing mechanisms: new targets for treating insulin-linked disorders? Biochemical Society Transactions 35: 1215-1217.
35. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, et al. (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136: 521-534.
36. Bryk B, Hahn K, Cohen SM, Teleman AA, (2010) MAP4K3 regulates body size and metabolism in Drosophila. Dev Biol 344: 150-157.
37. Findlay GM, Yan L, Procter J, Mieulet V, Lamb RF, (2007) A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling. Biochem J 403: 13-20.
38. Resnik-Docampo M, de Celis JF, (2010) MAP4K3 is a component of the TORC1 signalling complex that modulates cell growth and viability in Drosophila melanogaster. PLoS One 6: e14528.
39. Byfield MP, Murray JT, Backer JM, (2005) hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 280: 33076-33082.
40. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, et al. (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A 102: 14238-14243.
41. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, et al. (2011) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H-ATPase. Science 334: 678-683.
42. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, et al. (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465: 942-946.
43. Boll M, Daniel H, Gasnier B, (2004) The SLC36 family: proton-coupled transporters for the absorption of selected amino acids from extracellular and intracellular proteolysis. Pflugers Arch- Eur J Physiol 447: 776-779.
44. Broer S, (2008) Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology (Bethesda) 23: 95-103.
45. Thwaites DT, Anderson CM, (2011) The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br J Pharmacol 164: 1802-1816.
46. Heublein S, Kazi S, Ögmundsdóttir MH, Attwood EV, Kala S, et al. (2010) Proton-assisted amino-acid transporters are conserved regulators of proliferation and amino-acid-dependent mTORC1 activation. Oncogene 29: 4068-4079.
47. Gao M, Kaiser CA, (2006) A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast. Nature Cell Biology 8: 657-667.
48. Wreden CC, Johnson J, Tran C, Seal RP, Copenhagen DR, et al. (2003) The H+-coupled electrogenic lysosomal amino acid transporter LYAAT1 localizes to the axon and plasma membrane of hippocampal neurons. J Neurosci 23: 1265-1275.
49. Goberdhan DCI, Meredith D, Boyd CAR, Wilson C, (2005) PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids. Development 132: 2365-2375.
50. Brand AH, Perrimon N, (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118: 401-415.
51. Vereshchagina N, Ramel MC, Bitoun E, Wilson C, (2008) The protein phosphatase PP2A-B' subunit Widerborst is a negative regulator of cytoplasmic activated Akt and lipid metabolism in Drosophila. J Cell Sci 121: 3383-3392.
52. Radimerski T, Montagne J, Hemmings-Mieszczak M, Thomas G, (2002) Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes and Development 16: 2627-2632.
53. Radimerski T, Montagne J, Rintelen F, Stocker H, van der Kaay J, et al. (2002) dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nat Cell Biol 4: 251-255.
54. Dorn M, Weiwad M, Markwardt F, Laug L, Rudolph R, et al. (2009) Identification of a disulfide bridge essential for transport function of the human proton-coupled amino acid transporter hPAT1. J Biol Chem 284: 22123-22132.
55. Reiling JH, Hafen E, (2004) The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 18: 2879-2892.
56. Juhász G, Hill JH, Yan Y, Sass M, Baehrecke EH, et al. (2008) The class III PI(3)K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila. The Journal of Cell Biology 181: 655-666.
57. Patel PH, Thapar N, Guo L, Martinez M, Maris J, et al. (2003) Drosophila Rheb GTPase is required for cell cycle progression and cell growth. J Cell Sci 116: 3601-3610.
58. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, et al. (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5: 566-571.
59. Potter CJ, Pedraza LG, Xu T, (2002) Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 4: 658-665.
60. Goberdhan DCI, Paricio N, Goodman EC, Mlodzik M, Wilson C, (1999) Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev 13: 3244-3258.
61. Newsome TP, Asling B, Dickson BJ, (2000) Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics. Development 127: 851-860.
62. Wucherpfennig T, Wilsch-Brauninger M, Gonzalez-Gaitan M, (2003) Role of Drosophila Rab5 during endosomal trafficking at the synapse and evoked neurotransmitter release. J Cell Biol 161: 609-624.
63. Moline MM, Southern C, Bejsovec A, (1999) Directionality of wingless protein transport influences epidermal patterning in the Drosophila embryo. Development 126: 4375-4384.
64. Boll M, Foltz M, Rubio-Aliaga I, Kottra G, Daniel H, (2002) Functional characterization of two novel mammalian electrogenic proton-dependent amino acid cotransporters. J Biol Chem 277: 22966-22973.
65. Chen Z, Fei YJ, Anderson CM, Wake KA, Miyauchi S, et al. (2003) Structure, function and immunolocalization of a proton-coupled amino acid transporter (hPAT1) in the human intestinal cell line Caco-2. J Physiol 546: 349-361.
66. Rubio-Aliaga I, Boll M, Weisenhorn DMV, Foltz M, Kottra G, et al. (2004) The Proton/Amino Acid Cotransporter PAT2 Is Expressed in Neurons with a Different Subcellular Localization than Its Paralog PAT1. The Journal of Biological Chemistry 279: 2754-2760.
67. Sagne C, Agulhon C, Ravassard P, Darmon M, Hamon M, et al. (2001) Identification and characterization of a lysosomal transporter for small neutral amino acids. Proc Natl Acad Sci U S A 98: 7206-7211.
68. Sautin YY, Lu M, Gaugler A, Zhang L, Gluck SL, (2005) Phosphatidylinositol 3-kinase-mediated effects of glucose on vacuolar H+-ATPase assembly, translocation, and acidification of intracellular compartments in renal epithelial cells. Mol Cell Biol 25: 575-589.
69. Moreau K, Luo S, Rubinsztein DC, (2010) Cytoprotective roles for autophagy. Curr Opin Cell Biol 22: 206-211.
70. Turcotte S, Giaccia AJ, (2010) Targeting cancer cells through autophagy for anticancer therapy. Curr Opin Cell Biol 22: 246-251.
71. Pillai SM, Meredith D, (2011) SLC36A4 (hPAT4) is a high affinity amino acid transporter when expressed in Xenopus laevis oocytes. J Biol Chem 286: 2455-2460.
72. Toba G, Ohsako T, Miyata N, Ohtsuka T, Seong KH, et al. (1999) The gene search system. A method for efficient detection and rapid molecular identification of genes in Drosophila melanogaster. Genetics 151: 725-737.
73. Chintapalli VR, Wang J, Dow JA, (2007) Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nat Genet 39: 715-720.