Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of rag gtpases

Journal of Cell Biology

Volumn 202, Issue 7, 2013, Pages 1107-1122

  Petit, Constance S ^a   Roczniak Ferguson, Agnes ^a   Ferguson, Shawn M ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ESTRONE; FOLLICULIN INTERACTING PROTEIN 1; GUANOSINE TRIPHOSPHATASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MEMBRANE PROTEIN; RAG GTPASE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR EB; UNCLASSIFIED DRUG;

ARTICLE; CELL FUNCTION; CELL STIMULATION; CELL SURFACE; CONTROLLED STUDY; HUMAN; HUMAN CELL; LYSOSOME; PHOSPHORYLATION; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DEPLETION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN PURIFICATION; SIGNAL TRANSDUCTION; TRANSCRIPTION INITIATION;

AMINO ACIDS; BASIC HELIX-LOOP-HELIX LEUCINE ZIPPER TRANSCRIPTION FACTORS; BLOTTING, WESTERN; CARRIER PROTEINS; CYTOPLASM; FLUORESCENT ANTIBODY TECHNIQUE; HUMANS; IMMUNOPRECIPITATION; LYSOSOMES; MONOMERIC GTP-BINDING PROTEINS; MULTIPROTEIN COMPLEXES; PROTO-ONCOGENE PROTEINS; RECOMBINANT PROTEINS; RNA, SMALL INTERFERING; TOR SERINE-THREONINE KINASES; TUMOR SUPPRESSOR PROTEINS;

EID: 84886871016     PISSN: 00219525     EISSN: 15408140     Source Type: Journal    
DOI: 10.1083/jcb.201307084     Document Type: Article

References (70)

1. Allaire, P.D., A.L. Marat, C. Dall'Armi, G. Di Paolo, P.S. McPherson, and B. Ritter. 2010. The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes. Mol. Cell. 37:370-382. http://dx.doi.org/10.1016/j.molcel.2009.12.037
2. Baba, M., S.B. Hong, N. Sharma, M.B. Warren, M.L. Nickerson, A. Iwamatsu, D. Esposito, W.K. Gillette, R.F. Hopkins III, J.L. Hartley, et al. 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. 103:15552-15557. http://dx.doi.org/10.1073/pnas.0603781103
3. Bar-Peled, L., L.D. Schweitzer, R. Zoncu, and D.M. Sabatini. 2012. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 150:1196-1208. http://dx.doi.org/10.1016/j.cell.2012.07.032
4. Bar-Peled, L., L. Chantranupong, A.D. Cherniack, W.W. Chen, K.A. Ottina, B.C. Grabiner, E.D. Spear, S.L. Carter, M. Meyerson, and D.M. Sabatini. 2013. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 340:1100-1106. http://dx.doi.org/10.1126/science.1232044
5. Betschinger, J., J. Nichols, S. Dietmann, P.D. Corrin, P.J. Paddison, and A. Smith. 2013. Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell. 153:335-347. http://dx.doi.org/10.1016/j.cell.2013.03.012
6. Bonfils, G., M. Jaquenoud, S. Bontron, C. Ostrowicz, C. Ungermann, and C. De Virgilio. 2012. Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol. Cell. 46:105-110. http://dx.doi.org/10.1016/j.molcel.2012.02.009
7. Carpenter, A.E., T.R. Jones, M.R. Lamprecht, C. Clarke, I.H. Kang, O. Friman, D.A. Guertin, J.H. Chang, R.A. Lindquist, J. Moffat, et al. 2006. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7:R100. http://dx.doi.org/10.1186/gb-2006-7-10-r100
8. Cash, T.P., J.J. Gruber, T.R. Hartman, E.P. Henske, and M.C. Simon. 2011. Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFβ-mediated transcription. Oncogene. 30:2534-2546. http://dx.doi.org/10.1038/onc.2010.628
9. Cerny, J., Y. Feng, A. Yu, K. Miyake, B. Borgonovo, J. Klumperman, J. Meldolesi, P.L. McNeil, and T. Kirchhausen. 2004. The small chemical vacuolin-1 inhibits Ca(2+)-dependent lysosomal exocytosis but not cell resealing. EMBO Rep. 5:883-888. http://dx.doi.org/10.1038/sj.embor.7400243
10. Chan, T.F., J. Carvalho, L. Riles, and X.F. Zheng. 2000. A chemical genomics approach toward understanding the global functions of the target of rapamycin protein (TOR). Proc. Natl. Acad. Sci. USA. 97:13227-13232. http://dx.doi.org/10.1073/pnas.240444197
11. Chen, F., S.M. Pruett-Miller, Y. Huang, M. Gjoka, K. Duda, J. Taunton, T.N. Collingwood, M. Frodin, and G.D. Davis. 2011. High-frequency genome editing using ssDNA oligonucleotides with zinc-finger nucleases. Nat. Methods. 8:753-755. http://dx.doi.org/10.1038/nmeth.1653
12. Chen, J., K. Futami, D. Petillo, J. Peng, P. Wang, J. Knol, Y. Li, S.K. Khoo, D. Huang, C.N. Qian, et al. 2008. Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia. PLoS ONE. 3:e3581. http://dx.doi.org/10.1371/journal.pone.0003581
13. Dazert, E., and M.N. Hall. 2011. mTOR signaling in disease. Curr. Opin. Cell Biol. 23:744-755. http://dx.doi.org/10.1016/j.ceb.2011.09.003
14. Dokudovskaya, S., F. Waharte, A. Schlessinger, U. Pieper, D.P. Devos, I.M. Cristea, R. Williams, J. Salamero, B.T. Chait, A. Sali, et al. 2011. A conserved coatomer-related complex containing Sec13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae. Mol. Cell. Proteomics. 10:006478.
15. Durán, R.V., W. Oppliger, A.M. Robitaille, L. Heiserich, R. Skendaj, E. Gottlieb, and M.N. Hall. 2012. Glutaminolysis activates Rag-mTORC1 signaling. Mol. Cell. 47:349-358. http://dx.doi.org/10.1016/j.molcel.2012.05.043
16. Falcón-Pérez, J.M., R. Nazarian, C. Sabatti, and E.C. Dell'Angelica. 2005. Distribution and dynamics of Lamp1-containing endocytic organelles in fibroblasts deficient in BLOC-3. J. Cell Sci. 118:5243-5255. http://dx.doi.org/10.1242/jcs.02633
17. Gao, M., and C.A. Kaiser. 2006. A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast. Nat. Cell Biol. 8:657-667. http://dx.doi.org/10.1038/ncb1419
18. Han, J.M., S.J. Jeong, M.C. Park, G. Kim, N.H. Kwon, H.K. Kim, S.H. Ha, S.H. Ryu, and S. Kim. 2012. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell. 149:410-424. http://dx.doi.org/10.1016/j.cell.2012.02.044
19. Haq, R., and D.E. Fisher. 2011. Biology and clinical relevance of the micropthalmia family of transcription factors in human cancer. J. Clin. Oncol. 29:3474-3482. http://dx.doi.org/10.1200/JCO.2010.32.6223
20. Hartman, T.R., E. Nicolas, A. Klein-Szanto, T. Al-Saleem, T.P. Cash, M.C. Simon, and E.P. Henske. 2009. The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis. Oncogene. 28:1594-1604. http://dx.doi.org/10.1038/onc.2009.14
21. Hasumi, Y., M. Baba, R. Ajima, H. Hasumi, V.A. Valera, M.E. Klein, D.C. Haines, M.J. Merino, S.B. Hong, T.P. Yamaguchi, et al. 2009. Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc. Natl. Acad. Sci. USA. 106:18722-18727. http://dx.doi.org/10.1073/pnas.0908853106
22. Hemesath, T.J., E. Steingrímsson, G. McGill, M.J. Hansen, J. Vaught, C.A. Hodgkinson, H. Arnheiter, N.G. Copeland, N.A. Jenkins, and D.E. Fisher. 1994. microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev. 8:2770-2780. http://dx.doi.org/10.1101/gad.8.22.2770
23. Hillenmeyer, M.E., E. Fung, J. Wildenhain, S.E. Pierce, S. Hoon, W. Lee, M. Proctor, R.P. St Onge, M. Tyers, D. Koller, et al. 2008. The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science. 320:362-365. http://dx.doi.org/10.1126/science.1150021
24. Hong, S.B., H. Oh, V.A. Valera, M. Baba, L.S. Schmidt, and W.M. Linehan. 2010. Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS ONE. 5:e15793. http://dx.doi.org/10.1371/journal.pone.0015793
25. Hong, S.B., H. Oh, V.A. Valera, J. Stull, D.T. Ngo, M. Baba, M.J. Merino, W.M. Linehan, and L.S. Schmidt. 2010. Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Mol. Cancer. 9:160. http://dx.doi.org/10.1186/1476-4598-9-160
26. Hudon, V., S. Sabourin, A.B. Dydensborg, V. Kottis, A. Ghazi, M. Paquet, K. Crosby, V. Pomerleau, N. Uetani, and A. Pause. 2010. Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin. J. Med. Genet. 47:182-189. http://dx.doi.org/10.1136/jmg.2009.072009
27. Inoki, K., Y. Li, T. Xu, and K.L. Guan. 2003. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17:1829-1834. http://dx.doi.org/10.1101/gad.1110003
28. Inoki, K., J. Kim, and K.L. Guan. 2012. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52:381-400. http://dx.doi.org/10.1146/annurev-pharmtox-010611-134537
29. Kim, D.H., D.D. Sarbassov, S.M. Ali, R.R. Latek, K.V. Guntur, H. Erdjument- Bromage, P. Tempst, and D.M. Sabatini. 2003. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell. 11:895-904. http://dx.doi.org/10.1016/S1097-2765(03)00114-X
30. Kim, E., P. Goraksha-Hicks, L. Li, T.P. Neufeld, and K.L. Guan. 2008. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10:935-945. http://dx.doi.org/10.1038/ncb1753
31. Kim, Y.M., M. Stone, T.H. Hwang, Y.G. Kim, J.R. Dunlevy, T.J. Griffin, and D.H. Kim. 2012. SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling. Mol. Cell. 46:833-846. http://dx.doi.org/10.1016/j.molcel.2012.04.007
32. Laplante, M., and D.M. Sabatini. 2012. mTOR signaling in growth control and disease. Cell. 149:274-293. http://dx.doi.org/10.1016/j.cell.2012.03.017
33. Levine, T.P., R.D. Daniels, A.T. Gatta, L.H. Wong, and M.J. Hayes. 2013. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics. 29:499-503. http://dx.doi.org/10.1093/bioinformatics/bts725
34. Linehan, W.M. 2012. Genetic basis of kidney cancer: role of genomics for the development of disease-based therapeutics. Genome Res. 22:2089-2100. http://dx.doi.org/10.1101/gr.131110.111
35. Liu, W., Z. Chen, Y. Ma, X. Wu, Y. Jin, and S. Hou. 2013. Genetic characterization of the Drosophila birt-hogg-dubé syndrome gene. PLoS ONE. 8:e65869. http://dx.doi.org/10.1371/journal.pone.0065869
36. Loewith, R., E. Jacinto, S. Wullschleger, A. Lorberg, J.L. Crespo, D. Bonenfant, W. Oppliger, P. Jenoe, and M.N. Hall. 2002. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell. 10:457-468. http://dx.doi.org/10.1016/S1097-2765 (02)00636-6
37. Luijten, M.N., S.G. Basten, T. Claessens, M. Vernooij, C.L. Scott, R. Janssen, J.A. Easton, M.A. Kamps, M. Vreeburg, J.L. Broers, et al. 2013. Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum. Mol. Genet.
38. Ma, X.M., and J. Blenis. 2009. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10:307-318. http://dx.doi.org/10.1038/nrm2672
39. Mali, P., L. Yang, K.M. Esvelt, J. Aach, M. Guell, J.E. DiCarlo, J.E. Norville, and G.M. Church. 2013. RNA-guided human genome engineering via Cas9. Science. 339:823-826. http://dx.doi.org/10.1126/science.1232033
40. Marat, A.L., M.S. Ioannou, and P.S. McPherson. 2012. Connecdenn 3/DENND1C binds actin linking Rab35 activation to the actin cytoskeleton. Mol. Biol. Cell. 23:163-175. http://dx.doi.org/10.1091/mbc. E11-05-0474
41. Martina, J.A., and R. Puertollano. 2013. Rag GTPases mediate amino aciddependent recruitment of TFEB and MITF to lysosomes. J. Cell Biol. 200:475-491. http://dx.doi.org/10.1083/jcb.201209135
42. Martina, J.A., Y. Chen, M. Gucek, and R. Puertollano. 2012. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 8:903-914. http://dx.doi.org/10.4161/auto.19653
43. Mihaylova, M.M., and R.J. Shaw. 2011. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13:1016-1023. http://dx.doi.org/10.1038/ncb2329
44. Neklesa, T.K., and R.W. Davis. 2009. A genome-wide screen for regulators of TORC1 in response to amino acid starvation reveals a conserved Npr2/3 complex. PLoS Genet. 5:e1000515. http://dx.doi.org/10.1371/journal.pgen.1000515
45. Nickerson, M.L., M.B. Warren, J.R. Toro, V. Matrosova, G. Glenn, M.L. Turner, P. Duray, M. Merino, P. Choyke, C.P. Pavlovich, et al. 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. 2:157-164. http://dx.doi.org/10.1016/S1535-6108(02)00104-6
46. Nishii, T., M. Tanabe, R. Tanaka, T. Matsuzawa, K. Okudela, A. Nozawa, Y. Nakatani, and M. Furuya. 2013. Unique mutation, accelerated mTOR signaling and angiogenesis in the pulmonary cysts of Birt-Hogg-Dubé syndrome. Pathol. Int. 63:45-55. http://dx.doi.org/10.1111/pin.12028
47. Nookala, R.K., L. Langemeyer, A. Pacitto, B. Ochoa-Montaño, J.C. Donaldson, B.K. Blaszczyk, D.Y. Chirgadze, F.A. Barr, J.F. Bazan, and T.L. Blundell. 2012. Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open Biol. 2:120071. http://dx.doi.org/10.1098/rsob.120071
48. O'Rourke, E.J., and G. Ruvkun. 2013. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat. Cell Biol. 15:668-676. http://dx.doi.org/10.1038/ncb2741
49. Ögmundsdóttir, M.H., S. Heublein, S. Kazi, B. Reynolds, S.M. Visvalingam, M.K. Shaw, and D.C. Goberdhan. 2012. Proton-assisted amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes. PLoS ONE. 7:e36616. http://dx.doi.org/10.1371/journal.pone.0036616
50. Panchaud, N., M.P. Péli-Gulli, and C. De Virgilio. 2013. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal. 6:ra42. http://dx.doi.org/10.1126/scisignal.2004112
51. Peña-Llopis, S., S. Vega-Rubin-de-Celis, J.C. Schwartz, N.C. Wolff, T.A. Tran, L. Zou, X.J. Xie, D.R. Corey, and J. Brugarolas. 2011. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30:3242-3258. http://dx.doi.org/10.1038/emboj.2011.257
52. Roberg, K.J., S. Bickel, N. Rowley, and C.A. Kaiser. 1997. Control of amino acid permease sorting in the late secretory pathway of Saccharomyces cerevisiae by SEC13, LST4, LST7 and LST8. Genetics. 147:1569-1584.
53. Roczniak-Ferguson, A., C.S. Petit, F. Froehlich, S. Qian, J. Ky, B. Angarola, T.C. Walther, and S.M. Ferguson. 2012. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5:ra42. http://dx.doi.org/10.1126/scisignal.2002790
54. Sancak, Y., T.R. Peterson, Y.D. Shaul, R.A. Lindquist, C.C. Thoreen, L. Bar-Peled, and D.M. Sabatini. 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 320:1496-1501. http://dx.doi.org/10.1126/science.1157535
55. Sancak, Y., L. Bar-Peled, R. Zoncu, A.L. Markhard, S. Nada, and D.M. Sabatini. 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 141:290-303. http://dx.doi.org/10.1016/j.cell.2010.02.024
56. Sardiello, M., M. Palmieri, A. di Ronza, D.L. Medina, M. Valenza, V.A. Gennarino, C. Di Malta, F. Donaudy, V. Embrione, R.S. Polishchuk, et al. 2009. A gene network regulating lysosomal biogenesis and function. Science. 325:473-477.
57. Settembre, C., R. Zoncu, D.L. Medina, F. Vetrini, S. Erdin, S. Erdin, T. Huynh, M. Ferron, G. Karsenty, M.C. Vellard, et al. 2012. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31:1095-1108. http://dx.doi.org/10.1038/emboj.2012.32
58. Settembre, C., R. De Cegli, G. Mansueto, P.K. Saha, F. Vetrini, O. Visvikis, T. Huynh, A. Carissimo, D. Palmer, T.J. Klisch, et al. 2013. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15:647-658. http://dx.doi.org/10.1038/ncb2718
59. Singh, S.R., W. Zhen, Z. Zheng, H. Wang, S.W. Oh, W. Liu, B. Zbar, L.S. Schmidt, and S.X. Hou. 2006. The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance. Oncogene. 25:5933-5941. http://dx.doi.org/10.1038/sj.onc.1209593
60. Svensson, M.A. 1991. Increased sensitivity of the indirect immunofluorescence method by use of a tertiary fluorochrome-labeled antibody. J. Histochem. Cytochem. 39:235-237. http://dx.doi.org/10.1177/39.2.1987267
61. Takagi, Y., T. Kobayashi, M. Shiono, L. Wang, X. Piao, G. Sun, D. Zhang, M. Abe, Y. Hagiwara, K. Takahashi, and O. Hino. 2008. Interaction of folliculin(Birt-Hogg-Dubé gene product) with a novel Fnip1-like(FnipL/Fnip2) protein. Oncogene. 27:5339-5347. http://dx.doi.org/10.1038/onc.2008.261
62. Tee, A.R., and A. Pause. 2012. Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin. Fam. Cancer.
63. Thoreen, C.C., S.A. Kang, J.W. Chang, Q. Liu, J. Zhang, Y. Gao, L.J. Reichling, T. Sim, D.M. Sabatini, and N.S. Gray. 2009. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284:8023-8032. http://dx.doi.org/10.1074/jbc. M900301200
64. van Slegtenhorst, M., D. Khabibullin, T.R. Hartman, E. Nicolas, W.D. Kruger, and E.P. Henske. 2007. The Birt-Hogg-Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe. J. Biol. Chem. 282:24583-24590. http://dx.doi.org/10.1074/jbc. M700857200
65. Vazquez, F., J.H. Lim, H. Chim, K. Bhalla, G. Girnun, K. Pierce, C.B. Clish, S.R. Granter, H.R. Widlund, B.M. Spiegelman, and P. Puigserver. 2013. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell. 23:287-301. http://dx.doi.org/10.1016/j.ccr.2012.11.020
66. Wauson, E.M., E. Zaganjor, A.Y. Lee, M.L. Guerra, A.B. Ghosh, A.L. Bookout, C.P. Chambers, A. Jivan, K. McGlynn, M.R. Hutchison, et al. 2012. The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy. Mol. Cell. 47:851-862. http://dx.doi.org/10.1016/j.molcel.2012.08.001
67. Wu, X., M.J. Bradley, Y. Cai, D. Kümmel, E.M. De La Cruz, F.A. Barr, and K.M. Reinisch. 2011. Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate. Proc. Natl. Acad. Sci. USA. 108:18672-18677. http://dx.doi.org/10.1073/pnas.1110415108
68. Yoshimura, S., A. Gerondopoulos, A. Linford, D.J. Rigden, and F.A. Barr. 2010. Family-wide characterization of the DENN domain Rab GDPGTP exchange factors. J. Cell Biol. 191:367-381. http://dx.doi.org/10.1083/jcb.201008051
69. Zhang, D., L.M. Iyer, F. He, and L. Aravind. 2012. Discovery of novel DENN proteins: implications for the evolution of eukaryotic intracellular membrane structures and human disease. Front Genet. 3:283.
70. Zoncu, R., L. Bar-Peled, A. Efeyan, S. Wang, Y. Sancak, and D.M. Sabatini. 2011. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 334:678-683. http://dx.doi.org/10.1126/science.1207056