MTOR signaling in lymphangioleiomyomatosis

Lymphatic Research and Biology

Volumn 8, Issue 1, 2010, Pages 33-42

  Kristof, Arnold S ^a  

^a MCGILL UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN;

CELL GROWTH; CELL PROLIFERATION; CONGENITAL TUMOR; ENZYME ACTIVITY; HUMAN; LUNG DISEASE; LYMPHANGIOLEIOMYOMATOSIS; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN INTERACTION; RESPIRATORY FAILURE; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LYMPHANGIOLEIOMYOMATOSIS; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION;

EID: 77949786243     PISSN: 15396851     EISSN: None     Source Type: Journal    
DOI: 10.1089/lrb.2009.0019     Document Type: Review

References (144)

1. Pan D, Dong J, Zhang Y, Gao X. Tuberous sclerosis complex: from Drosophila to human disease. Trends Cell Biol 2004; 14:78-85.
2. Goncharova EA, Goncharov DA, Eszterhas A, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 2002;277:30958-30967.
3. el Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 2003;361:1348-1349.
4. Pacheco-Rodriguez G, Kristof AS, Stevens LA, Zhang Y, Crooks D, Moss J. Giles F. Filley Lecture. Genetics and gene expression in lymphangioleiomyomatosis. Chest 2002;121: 56S-60S.
5. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 2005;37: 19-24.
6. Shaw RJ. Glucose metabolism and cancer. Curr Opin Cell Biol 2006;18:598-608.
7. DeBerardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: Metabolism and tumor cell growth. Curr Opin Genet Dev 2008;18:54-61.
8. Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12=rapamycin complex. Proc Natl Acad Sci USA 1994;91:12574-12578.
9. Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994;369:756-758.
10. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994;78:35-43.
11. Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003;4:117-126.
12. Alessi DR, Pearce LR, Garcia-Martinez JM. New insights into mTOR signaling: mTORC2 and beyond. Sci Signal 2009;2:e27.
13. Daub H, Olsen JV, Bairlein M, et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell 2008;3:438-448.
14. Dephoure N, Zhou C, Villen J, et al. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci USA 2008;105: 10762-10767.
15. Peterson RT, Beal PA, Comb MJ, Schreiber SL. FKBP12- rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem 2000;275:7416-7423.
16. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal 2009;2:e24.
17. Yu K, Toral-Barza L, Shi C, et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 2009;69:6232-6240.
18. Kristof AS, Pacheco-Rodriguez G, Schremmer B, Moss J. LY303511 acts via PI3-kinase independent pathways to inhibit cell proliferation via mTOR- and non-mTOR-dependent mechanisms. J Pharmacol Exp Ther 2005;314:1134-1143.
19. Sekulic A, Hudson CC, Homme JL, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen- stimulated and transformed cells. Cancer Res 2000;60: 3504-3513.
20. Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: Identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 1999;344:427-431.
21. Acosta-Jaquez HA, Keller JA, Foster KG, et al. Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. Mol Cell Biol 2009;29:4308-4324.
22. Zhang X, Shu L, Hosoi H, Murti KG, Houghton PJ. Predominant nuclear localization of mammalian target of rapamycin in normal and malignant cells in culture. J Biol Chem 2002;277:28127-28134.
23. Bachmann RA, Kim JH, Wu AL, Park IH, Chen J. A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem 2006;281:7357-7363.
24. Liu X, Zheng XF. ER and Golgi localization sequences for mammalian target of rapamycin (mTOR). Mol Biol Cell 2007;18:1073-1082.
25. Ozcan U, Ozcan L, Yilmaz E, et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 2008;29:541-551.
26. Drenan RM, Liu X, Bertram PG, Zheng XF. FKBP12- rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus. J Biol Chem 2004;279: 772-778.
27. Puria R, Zurita-Martinez SA, Cardenas ME. Nuclear translocation of Gln3 in response to nutrient signals requires Golgi-to-endosome trafficking in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 2008;105:7194-7199.
28. Desai BN, Myers BR, Schreiber SL. FKBP12-rapamycinassociated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc Natl Acad Sci USA 2002;99:4319-4324.
29. Schieke SM, Phillips D, McCoy JP, Jr., et al. The mTOR pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 2006;281:27643-27652.
30. Sarbassov DD, Sabatini DM. Redox regulation of the nutrient- sensitive raptor-mTOR pathway and complex. J Biol Chem 2005;280:39505-39509.
31. Dames SA, Mulet JM, Rathgeb-Szabo K, Hall MN, Grzesiek S. The solution structure of the FATC domain of the protein kinase target of rapamycin suggests a role for redoxdependent structural and cellular stability. J Biol Chem 2005;280:20558-20564.
32. Jacinto E. What controls TOR? IUBMB Life 2008;60:483-496.
33. Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002;10:457-468.
34. Lee VH, Healy T, Fonseca BD, Hayashi A, Proud CG. Analysis of the regulatory motifs in eukaryotic initiation factor 4E-binding protein 1. FEBS J 2008;275:2185-2199.
35. Schalm SS, Fingar DC, Sabatini DM, Blenis J. TOS Motifmediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 2003;13:797-806.
36. Nojima H, Tokunaga C, Eguchi S, et al. 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 2003;278:15461-15464.
37. Jacinto E, Lorberg A. TOR regulation of AGC kinases in yeast and mammals. Biochem J 2008;410:19-37.
38. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J 2008;27:1919-1931.
39. Facchinetti V, Ouyang W, Wei H, et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 2008;27:1932-1943.
40. Jacinto E, Facchinetti V, Liu D, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt pPhosphorylation and substrate specificity. Cell 2006;127:125-137.
41. Frias MA, Thoreen CC, Jaffe JD, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006;16:1865-1870.
42. Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 2007;405:513-522.
43. Thedieck K, Polak P, Kim ML, et al. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS ONE 2007;2:e1217.
44. Woo SY, Kim DH, Jun CB, et al. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 2007; 282:25604-25612.
45. Kim dH, Sarbassov dD, Ali SM, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003;11:895-904.
46. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005;15: 702-713.
47. Li Y, Inoki K, Guan KL. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol Cell Biol 2004;24:7965-7975.
48. Garami A, Zwartkruis FJ, Nobukuni T, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003;11:1457-1466.
49. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPaseactivating protein complex toward Rheb. Curr Biol 2003;13: 1259-1268.
50. Huang J, Dibble CC, Matsuzaki M, Manning BD. The TSC1- TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 2008;28:4104-4115.
51. Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009;37:217-222.
52. Oshiro N, Takahashi R, Yoshino K, et al. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J Biol Chem 2007;282:20329-20339.
53. Fonseca BD, Smith EM, Lee VH, MacKintosh C, Proud CG. PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J Biol Chem 2007;282:24514-24524.
54. Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007;25:903-915.
55. Vander HE, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007;9:316-323.
56. Bai X, Ma D, Liu A, et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 2007;318:977-980.
57. Rosner M, Hofer K, Kubista M, Hengstschlager M. Cell size regulation by the human TSC tumor suppressor proteins depends on PI3K and FKBP38. Oncogene 2003;22:4786-4798.
58. Ma D, Bai X, Guo S, Jiang Y. The switch I region of Rheb is critical for its interaction with FKBP38. J Biol Chem 2008; 283:25963-25970.
59. Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 2001;294:1942-1945.
60. Fang Y, Park IH, Wu AL, et al. PLD1 regulates mTOR signaling and mediates Cdc42 activation of S6K1. Curr Biol 2003;13:2037-2044.
61. Sun Y, Chen J. mTOR signaling: PLD takes center stage. Cell Cycle 2008;7:3118-3123.
62. Toschi A, Lee E, Xu L, Garcia A, Gadir N, Foster DA. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: A competition with rapamycin. Mol Cell Biol 2009;29:1411-1420.
63. Sancak Y, Sabatini DM. Rag proteins regulate amino-acidinduced mTORC1 signalling. Biochem Soc Trans 2009;37: 289-290.
64. Yan G, Shen X, Jiang Y. Rapamycin activates Tap42- associated phosphatases by abrogating their association with Tor complex 1. EMBO J 2006;25:3546-3555.
65. Rohde JR, Bastidas R, Puria R, Cardenas ME. Nutritional control via Tor signaling in Saccharomyces cerevisiae. Curr Opin Microbiol 2008;11:153-160.
66. Peterson RT, Desai BN, Hardwick JS, Schreiber SL. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc Natl Acad Sci USA 1999;96:4438-4442.
67. Nanahoshi M, Nishiuma T, Tsujishita Y, et al. Regulation of protein phosphatase 2A catalytic activity by alpha4 protein and its yeast homolog Tap42. Biochem Biophys Res Commun 1998;251:520-526.
68. Di Como CJ, Arndt KT. Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev 1996;10:1904-1916.
69. Inui S, Sanjo H, Maeda K, Yamamoto H, Miyamoto E, Sakaguchi N. Ig receptor binding protein 1 (alpha4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2A. Blood 1998;92:539-546.
70. Murata K, Wu J, Brautigan DL. B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci USA 1997;94:10624-10629.
71. Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 2009;1795:1-15.
72. Wang H, Jiang Y. The Tap42-protein phosphatase type 2A catalytic subunit complex is required for cell cycledependent distribution of actin in yeast. Mol Cell Biol 2003;23:3116-3125.
73. Kong M, Bui TV, Ditsworth D, et al. The PP2A-associated protein alpha 4 plays a critical role in the regulation of cell spreading and migration. J Biol Chem 2007;282:29712-29720.
74. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002;10:151-162.
75. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648-657.
76. Parker PJ. Protein kinase C phosphorylation: An introduction. Methods Mol Biol 2003;233:159-162.
77. Romanelli A, Dreisbach VC, Blenis J. Characterization of phosphatidylinositol 3-kinase-dependent phosphorylation of the hydrophobic motif site Thr(389) in p70 S6 kinase 1. J Biol Chem 2002;277:40281-40289.
78. Parekh D, Ziegler W, Yonezawa K, Hara K, Parker PJ. Mammalian TOR controls one of two kinase pathways acting upon nPKCdelta and nPKCepsilon. J Biol Chem 1999; 274:34758-34764.
79. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006;22:159-168.
80. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP=/mTOR. Proc Natl Acad Sci USA 2001;98:10314-10319.
81. Podsypanina K, Lee RT, Politis C, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc Natl Acad Sci USA 2001;98: 10320-10325.
82. Wendel HG, De SE, Fridman JS, et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 2004;428:332-337.
83. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-1101.
84. Manning BD, Logsdon MN, Lipovsky AI, Abbott D, Kwiatkowski DJ, Cantley LC. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 2005;19:1773-1778.
85. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004;14:1650-1656.
86. Easton JB, Kurmasheva RT, Houghton PJ. IRS-1: Auditing the effectiveness of mTOR inhibitors. Cancer Cell 2006;9:153-155.
87. Roux PP, Shahbazian D, Vu H, et al. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 2007;282:14056-14064.
88. Carriere A, Cargnello M, Julien LA, et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSKmediated raptor phosphorylation. Curr Biol 2008;18:1269-1277.
89. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005;121:179-193.
90. Distefano G, Boca M, Rowe I, et al. Polycystin-1 regulates ERKs-dependent phosphorylation of tuberin to control cell size through mTOR and its downstream rffectors S6K and 4EBP1. Mol Cell Biol 2009;29:2359-2371.
91. Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008;118:3065-3074.
92. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: A recipe for cancer growth. Genes Dev 2009;23: 537-548.
93. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-226.
94. Inoki K, Ouyang H, Zhu T, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006;126:955-968.
95. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115:577-590.
96. Mak BC, Kenerson HL, Aicher LD, Barnes EA, Yeung RS. Aberrant beta-catenin signaling in tuberous sclerosis. Am J Pathol 2005;167:107-116.
97. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8:387-398.
98. Ma MX, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009;10:307-318.
99. Petroulakis E, Mamane Y, Le Bacquer O, Shahbazian D, Sonenberg N. mTOR signaling: Implications for cancer and anticancer therapy. Br J Cancer 2006;94:195-199.
100. Sonenberg N. eIF4E, the mRNA cap-binding protein: From basic discovery to translational research. Biochem Cell Biol 2008;86:178-183.
101. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature 1990;345:544-547.
102. Rousseau D, Gingras AC, Pause A, Sonenberg N. The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth. Oncogene 1996;13:2415-2420.
103. Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001;21:952-965.
104. Kumar V, Pandey P, Sabatini D, et al. Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation. EMBO J 2000;19:1087-1097.
105. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008;416:375-385.
106. Jones KT, Greer ER, Pearce D, Ashrafi K. Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol 2009;7:e60.
107. Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G. Rictor/ TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev 2009;23:496-511.
108. Hong F, Larrea MD, Doughty C, Kwiatkowski DJ, Squillace R, Slingerland JM. mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell 2008;30:701-711.
109. Fielhaber JA, Han YS, Tan j, et al. Inactivation of mammalian target of rapamycin increases stat1 nuclear content and transcriptional activity in {alpha}4- and protein phosphatase 2A-dependent fashion. J Biol Chem 2009;284:24341-24353.
110. Kristof AS, Marks-Konczalik J, Billings E, Moss J. Stimulation of STAT1-dependent gene transcription by lipopolysaccharide and interferon-gamma is regulated by mammalian target of rapamycin. J Biol Chem 2003;278:33637-33644.
111. Platanias LC. Mechanisms of type-I- and type-II-interferonmediated signalling. Nat Rev Immunol 2005;5:375-386.
112. Nguyen DX, Bos PD, Massague J. Metastasis: From dissemination to organ-specific colonization. Nat Rev Cancer 2009;9:274-284.
113. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10:789-799.
114. Peng T, Golub TR, Sabatini DM. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol Cell Biol 2002;22:5575-5584.
115. Tsang CK, Zheng XF. TOR-in(g) the nucleus. Cell Cycle 2007;6:25-29.
116. Li H, Tsang CK, Watkins M, Bertram PG, Zheng XF. Nutrient regulates Tor1 nuclear localization and association with rDNA promoter. Nature 2006;442:1058-1061.
117. Yokogami K, Wakisaka S, Avruch J, Reeves SA. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol 2000;10:47-50.
118. Zhou J, Wulfkuhle J, Zhang H, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA 2007;104:16158-16563.
119. Goncharova EA, Goncharov DA, Chisolm A, et al. Interferon {beta} augments TSC2-dependent inhibition of TSC2- null ELT3 and human LAM-derived cell proliferation. Mol Pharmacol 2007;73:778-788.
120. Regis G, Pensa S, Boselli D, Novelli F, Poli V. Ups and downs: The STAT1:STAT3 seesaw of interferon and gp130 receptor signalling. Semin Cell Dev Biol 2008;19:351-359.
121. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006;441:431-436.
122. Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev 2008;22:1490-1500.
123. Ghosh S, Tergaonkar V, Rothlin CV, et al. Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival. Cancer Cell 2006;10:215-226.
124. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 2007;450:736-740.
125. Semenza GL. Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life 2008;60:591-597.
126. Land SC, Tee AR. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signalingmotif. J Biol Chem 2007;282:20534-20543.
127. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 2003;4:147-158.
128. Brugarolas J, Lei K, Hurley RL et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18:2893-2904.
129. Morselli E, Galluzzi L, Kepp O, et al. Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta 2009; 1793:1524-1532.
130. Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009;20:1992-2003.
131. Ganley IG, Lam dH, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediatesmTOR signaling and is essential for autophagy. J Biol Chem 2009;284:12297-12305.
132. Goncharova EA, Goncharov DA, Lim PN, Noonan D, Krymskaya VP. Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2006;34:473-480.
133. Goncharova E, Goncharov D, Noonan D, Krymskaya VP. TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. J Cell Biol 2004;167:1171-1182.
134. Hernandez-Negrete I, Carretero-Ortega J, Rosenfeldt H, et al. P-Rex1 links mTOR signaling to Rac activation and cell migration. J Biol Chem 2007;282:23708-23715.
135. Schewe DM, guirre-Ghiso JA. ATF6{alpha}-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc Natl Acad Sci USA 2008;105:10519-10524.
136. Yu JJ, Robb VA, Morrison TA, et al. Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proc Natl Acad Sci USA 2009;106:2635-2640.
137. Finlay GA, York B, Karas RH, et al. Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-beta and ERK-1/2. J Biol Chem 2004;279:23114-23122.
138. Yu J, Astrinidis A, Howard S, Henske EP. Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Am J Physiol Lung Cell Mol Physiol 2004;286:L694-L700.
139. Yu J, Henske EP. Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Cancer Res 2006;66:9461-9466.
140. Nien WL, Dauphinee SM, Moffat LD, Too CK. Overexpression of the mTOR alpha4 phosphoprotein activates protein phosphatase 2A and increases Stat1alpha binding to PIAS1. Mol Cell Endocrinol 2006;263:10-17.
141. Boudreau RT, Sangster SM, Johnson LM,Dauphinee S, LiAW, Too CK. Implication of alpha4 phosphoprotein and the rapamycin- sensitive mammalian target-of-rapamycin pathway in prolactin receptor signalling. J Endocrinol 2002;173:493-506.
142. Karbowniczek M, Robertson GP, Henske EP. Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization. J Biol Chem 2006;281:25447-25456.
143. Chen J, Zheng XF, Brown EJ, Schreiber SL. 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 1995;92:4947-4951.
144. Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996;273:239-242.