Platelet-derived growth factor/vascular endothelial growth factor receptor inactivation by sunitinib results in Tsc1/Tsc2-dependent inhibition of TORC1

Molecular and Cellular Biology

Volumn 33, Issue 19, 2013, Pages 3762-3779

  Tran, Tram Anh ^a,b,c   Kinch, Lisa ^b   Peña Llopis, Samuel ^a,b,c   Kockel, Lutz ^d   Grishin, Nick ^b   Jiang, Huaqi ^a   Brugarolas, James ^b,c  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^d STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADAPTOR PROTEIN; HETERODIMER; INSULIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATASE; PHOSPHOTRANSFERASE; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN CG32406; PROTEIN SH2; PROTEIN TSC1; S6 KINASE; SUNITINIB; TUBERIN; TUBULIN; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR;

ANIMAL CELL; ARTICLE; BLOOD CELL; CELL EXPANSION; CELL SURVIVAL; CELL TYPE; CONTROLLED STUDY; DROSOPHILA; DRUG RECEPTOR BINDING; DRUG SENSITIVITY; ENDOTHELIUM CELL; HUMAN; HUMAN CELL; IN VITRO STUDY; INSECT CELL; NONHUMAN; PRIORITY JOURNAL; RECEPTOR DOWN REGULATION; RNA INTERFERENCE;

AMINO ACID SEQUENCE; ANIMALS; ANTINEOPLASTIC AGENTS; BLOTTING, WESTERN; CELL CYCLE PROTEINS; CELL LINE; CELL PROLIFERATION; CELLS, CULTURED; DROSOPHILA PROTEINS; ENDOTHELIAL CELLS; HEMOCYTES; HUMANS; INDOLES; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MULTIPROTEIN COMPLEXES; MUTATION; PROTEIN STRUCTURE, TERTIARY; PYRROLES; RECEPTOR PROTEIN-TYROSINE KINASES; RNA INTERFERENCE; SEQUENCE HOMOLOGY, AMINO ACID; TOR SERINE-THREONINE KINASES; TUMOR SUPPRESSOR PROTEINS;

EID: 84886771587     PISSN: 02707306     EISSN: 10985549     Source Type: Journal    
DOI: 10.1128/MCB.01570-12     Document Type: Article

References (86)

1. Hoch RV, Soriano P. 2003. Roles of PDGF in animal development. Development 130:4769-4784.
2. Heldin CH, Westermark B. 1999. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol. Rev. 79:1283-1316.
3. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. 2006. VEGF receptor signalling-in control of vascular function. Nat. Rev. Mol. Cell Biol. 7:359-371.
4. Ferrara N, Gerber HP, LeCouter J. 2003. The biology of VEGF and its receptors. Nat. Med. 9:669-676.
5. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L. 2003. VEGFreceptor signal transduction. Trends Biochem. Sci. 28:488-494.
6. Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, Hong K, Marsters JC, Ferrara N. 2002. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417:954- 958.
7. Kissa K, Herbomel P. 2010. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464:112-115.
8. Bertrand JY, Chi NC, Santoso B, Teng S, Stainier DY, Traver D. 2010. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 464:108-111.
9. Boisset JC, van Cappellen W, Andrieu-Soler C, Galjart N, Dzierzak E, Robin C. 2010. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464:116-120.
10. Andrae J, Gallini R, Betsholtz C. 2008. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 22:1276-1312.
11. Jones AV, Cross NC. 2004. Oncogenic derivatives of platelet-derived growth factor receptors. Cell. Mol. Life Sci. 61:2912-2923.
12. Otrock ZK, Makarem JA, Shamseddine AI. 2007. Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol. Dis. 38:258-268.
13. Tallquist M, Kazlauskas A. 2004. PDGF signaling in cells and mice. Cytokine Growth Factor Rev. 15:205-213.
14. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K. 2001. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 20:4762-4773.
15. Padro T, Bieker R, Ruiz S, Steins M, Retzlaff S, Burger H, Buchner T, Kessler T, Herrera F, Kienast J, Muller-Tidow C, Serve H, Berdel WE, Mesters RM. 2002. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 16:1302-1310.
16. Antonescu CR, Yoshida A, Guo T, Chang NE, Zhang L, Agaram NP, Qin LX, Brennan MF, Singer S, Maki RG. 2009. KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res. 69:7175-7179.
17. Martin DE, Hall MN. 2005. The expanding TOR signaling network. Curr. Opin. Cell Biol. 17:158-166.
18. Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. 2009. Amino acid regulation of TOR complex 1. Am. J. Physiol. Endocrinol. Metab. 296:E592-602.
19. Yu Y, Sato JD. 1999. MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J. Cell. Physiol. 178:235-246.
20. Seko Y, Takahashi N, Tobe K, Ueki K, Kadowaki T, Yazaki Y. 1998. Vascular endothelial growth factor (VEGF) activates Raf-1, mitogenactivated protein (MAP) kinases, and S6 kinase (p90rsk) in cultured rat cardiac myocytes. J. Cell. Physiol. 175:239-246.
21. Ming XF, Burgering BM, Wennstrom S, Claesson-Welsh L, Heldin CH, Bos JL, Kozma SC, Thomas G. 1994. Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature 371:426-429.
22. Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J. 1994. PDGFand insulin-dependent pp70S6k activation mediated by phosphatidylinositol- 3-OH kinase. Nature 370:71-75.
23. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. 2005. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121:179-193.
24. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J. 2004. Tumorpromoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. U. S. A. 101:13489-13494.
25. Potter CJ, Pedraza LG, Xu T. 2002. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4:658-665.
26. Inoki K, Li Y, Zhu T, Wu J, Guan KL. 2002. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4:648- 657.
27. Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ. 2002. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J. Biol. Chem. 277: 35364-35370.
28. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. 2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol. Cell 10:151-162.
29. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. 2007. Insulin signalling tomTORmediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9:316-323.
30. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM. 2007. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25:903-915.
31. Wang L, Harris TE, Lawrence JC, Jr. 2008. Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J. Biol. Chem. 283:15619-15627.
32. 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. 282:20329-20339.
33. Dancey J. 2010. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol. 7:209-219.
34. Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, Fukuda JY, Chu JY, Nematalla A, Wang XY, Chen H, Sistla A, Luu TC, Tang F, Wei J, Tang C. 2003. Discovery of 5-5-fluoro-2-oxo-1,2-dihydroindol-(3Z)- ylidenemethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2- diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J. Med. Chem. 46:1116-1119.
35. Huang D, Ding Y, Li Y, Luo WM, Zhang ZF, Snider J, Vandenbeldt K, Qian CN, Teh BT. 2010. Sunitinib acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma. Cancer Res. 70:1053-1062.
36. Duchek P, Somogyi K, Jekely G, Beccari S, Rorth P. 2001. Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 107:17-26.
37. Cho NK, Keyes L, Johnson E, Heller J, Ryner L, Karim F, Krasnow MA. 2002. Developmental control of blood cell migration by the Drosophila VEGF pathway. Cell 108:865-876.
38. Bruckner K, Kockel L, Duchek P, Luque CM, Rorth P, Perrimon N. 2004. The PDGF/VEGF receptor controls blood cell survival in Drosophila. Dev. Cell 7:73-84.
39. Munier AI, Doucet D, Perrodou E, Zachary D, Meister M, Hoffmann JA, Janeway CA, Jr, Lagueux M. 2002. PVF2, a PDGF/VEGF-like growth factor, induces hemocyte proliferation in Drosophila larvae. EMBO Rep. 3:1195-1200.
40. Zettervall CJ, Anderl I, Williams MJ, Palmer R, Kurucz E, Ando I, Hultmark D. 2004. A directed screen for genes involved in Drosophila blood cell activation. Proc. Natl. Acad. Sci. U. S. A. 101:14192-14197.
41. Learte AR, Forero MG, Hidalgo A. 2008. Gliatrophic and gliatropic roles of PVF/PVR signaling during axon guidance. Glia 56:164-176.
42. Jekely G, Sung HH, Luque CM, Rorth P. 2005. Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration. Dev. Cell 9:197-207.
43. Ishimaru S, Ueda R, Hinohara Y, Ohtani M, Hanafusa H. 2004. PVR plays a critical role via JNK activation in thorax closure during Drosophila metamorphosis. EMBO J. 23:3984-3994.
44. Bond D, Foley E. 2009. A quantitative RNAi screen for JNK modifiers identifies Pvr as a novel regulator of Drosophila immune signaling. PLoS Pathog. 5:e1000655. doi:10.1371/journal.ppat.1000655.
45. Miron M, Lasko P, Sonenberg N. 2003. Signaling from Akt to FRAP/ TOR targets both 4E-BP and S6K in Drosophila melanogaster. Mol. Cell. Biol. 23:9117-9126.
46. Stocker H, Andjelkovic M, Oldham S, Laffargue M, Wymann MP, Hemmings BA, Hafen E. 2002. Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PHdomain mutation in Akt/PKB. Science 295:2088-2091.
47. 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.
48. Worby CA, Simonson-Leff N, Dixon JE. 2001. RNA interference of gene expression (RNAi) in cultured Drosophila cells. Sci. STKE 2001:pl1. doi: 10.1126/scisignal.952001pl1.
49. Wolff NC, Vega-Rubin-de-Celis S, Xie XJ, Castrillon DH, Kabbani W, Brugarolas J. 2011. Cell-type-dependent regulation of mTORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia. Mol. Cell. Biol. 31:1870-1884.
50. Crevel I, Crevel G, Gostan T, de Renty C, Coulon V, Cotterill S. 2011. Decreased MCM2-6 in Drosophila S2 cells does not generate significant DNA damage or cause a marked increase in sensitivity to replication interference. PLoS One 6:e27101. doi:10.1371/journal.pone.0027101.
51. Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J, Zhang X. 2010. Structural analysis and functional implications of the negative mTORC1 Regulator REDD1. Biochemistry 49:2491-2501.
52. Pena-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC, Wolff NC, Tran TA, Zou L, Xie XJ, Corey DR, Brugarolas J. 2011. Regulation of TFEB and V-ATPases by mTORC1. EMBO J. 30:3242-3258.
53. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG, Jr. 2004. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18:2893-2904.
54. Sivanand S, Pena-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J. 2012. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma. Sci. Transl. Med. 4:137ra175. doi:10.1126 /scitranslmed.3003649.
55. Katoh K, Toh H. 2008. Recent developments in the MAFFT multiple sequence alignment program. Brief Bioinform. 9:286-298.
56. Adachi J, Hasegawa M. 1992. MOLPHY, programs for molecular phylogenetics, I: PROTML, maximum likelihood inference of protein phylogeny. Institute of Statistical Mathematics, Tokyo, Japan.
57. Kiefer F, Arnold K, Kunzli M, Bordoli L, Schwede T. 2009. The SWISSMODEL repository and associated resources. Nucleic Acids Res. 37: D387-D392.
58. Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE, Thomas G. 1995. The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J. 14:5279-5287.
59. Fernandez-Almonacid R, Rosen OM. 1987. Structure and ligand specificity of the Drosophila melanogaster insulin receptor. Mol. Cell. Biol. 7:2718-2727.
60. Lizcano JM, Alrubaie S, Kieloch A, Deak M, Leevers SJ, Alessi DR. 2003. Insulin-induced Drosophila S6 kinase activation requires phosphoinositide 3-kinase and protein kinase B. Biochem. J. 374:297-306.
61. Sears HCR. 2004. Identification and characterization of proteins that bind the intracellular domain of PVR. PhD. thesis. Massachusetts Institute of Technology, Cambridge, MA.
62. Tari AM, Lopez-Berestein G. 2001. GRB2: a pivotal protein in signal transduction. Semin. Oncol. 28:142-147.
63. Werz C, Kohler K, Hafen E, Stocker H. 2009. The Drosophila SH2B family adaptor Lnk acts in parallel to chico in the insulin signaling pathway. PLoS Genet. 5:e1000596. doi:10.1371/journal.pgen.1000596.
64. Luschnig S, Krauss J, Bohmann K, Desjeux I, Nusslein-Volhard C. 2000. The Drosophila SHC adaptor protein is required for signaling by a subset of receptor tyrosine kinases. Mol. Cell 5:231-241.
65. Rawlings JS, Rennebeck G, Harrison SM, Xi R, Harrison DA. 2004. Two Drosophila suppressors of cytokine signaling (SOCS) differentially regulate JAK and EGFR pathway activities. BMC Cell Biol. 5:38. doi:10.1186 /1471-2121-5-38.
66. Rosin D, Schejter E, Volk T, Shilo BZ. 2004. Apical accumulation of the Drosophila PDGF/VEGF receptor ligands provides a mechanism for triggering localized actin polymerization. Development 131:1939 -1948.
67. Gajiwala KS, Wu JC, Christensen J, Deshmukh GD, Diehl W, DiNitto JP, English JM, Greig MJ, He YA, Jacques SL, Lunney EA, McTigue M, Molina D, Quenzer T, Wells PA, Yu X, Zhang Y, Zou A, Emmett MR, Marshall AG, Zhang HM, Demetri GD. 2009. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc. Natl. Acad. Sci. U. S. A. 106: 1542-1547.
68. Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, Fletcher CD, Corless CL, Fletcher JA. 2008. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J. Pathol. 216:64-74.
69. Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, Town A, McKinley A, Ou WB, Fletcher JA, Fletcher CD, Huang X, Cohen DP, Baum CM, Demetri GD. 2008. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J. Clin. Oncol. 26: 5352-5359.
70. Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, Leversha MA, Jeffrey PD, Desantis D, Singer S, Brennan MF, Maki RG, DeMatteo RP. 2005. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin. Cancer Res. 11:4182-4190.
71. McTigue M, Murray BW, Chen JH, Deng YL, Solowiej J, Kania RS. 2012. Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc. Natl. Acad. Sci. U. S. A. 109:18281-18289.
72. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y. 1998. Gain-offunction mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577-580.
73. Chompret A, Kannengiesser C, Barrois M, Terrier P, Dahan P, Tursz T, Lenoir GM, Bressac-De Paillerets B. 2004. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 126:318-321.
74. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA. 2003. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J. Clin. Oncol. 21:4342-4349.
75. Laine E, Chauvot de Beauchene I, Perahia D, Auclair C, Tchertanov L. 2011. Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms. PLoS Comput. Biol. 7:e1002068. doi:10.1371/journal.pcbi .1002068.
76. Zhang HM, Yu X, Greig MJ, Gajiwala KS, Wu JC, Diehl W, Lunney EA,Emmett MR, Marshall AG. 2010. Drug binding and resistance mechanism of KIT tyrosine kinase revealed by hydrogen/deuterium exchange FTICR mass spectrometry. Protein Sci. 19:703-715.
77. Senthil D, Ghosh Choudhury G, Bhandari BK, Kasinath BS. 2002. The type 2 vascular endothelial growth factor receptor recruits insulin receptor substrate-1 in its signalling pathway. Biochem. J. 368:49-56.
78. Miele C, Rochford JJ, Filippa N, Giorgetti-Peraldi S, Van Obberghen E. 2000. Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways. J. Biol. Chem. 275:21695-21702.
79. Poulaki V, Qin W, Joussen AM, Hurlbut P, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP. 2002. Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxiainducible factor-1α and VEGF. J. Clin. Invest. 109:805-815.
80. Bermont L, Lamielle F, Lorchel F, Fauconnet S, Esumi H, Weisz A, Adessi GL. 2001. Insulin up-regulates vascular endothelial growth factor and stabilizes its messengers in endometrial adenocarcinoma cells. J. Clin. Endocrinol. Metab. 86:363-368.
81. Guruharsha KG, Rual JF, Zhai B, Mintseris J, Vaidya P, Vaidya N, Beekman C, Wong C, Rhee DY, Cenaj O, McKillip E, Shah S, Stapleton M, Wan KH, Yu C, Parsa B, Carlson JW, Chen X, Kapadia B, Vijay-Raghavan K, Gygi SP, Celniker SE, Obar RA, Artavanis-Tsakonas S. 2011. A protein complex network of Drosophila melanogaster. Cell 147: 690-703.
82. Mondal BC, Mukherjee T, Mandal L, Evans CJ, Sinenko SA, Martinez-Agosto JA, Banerjee U. 2011. Interaction between differentiating celland niche-derived signals in hematopoietic progenitor maintenance. Cell 147:1589-1600.
83. Traver D, Zon LI. 2002. Walking the walk: migration and other common themes in blood and vascular development. Cell 108:731-734.
84. Holz A, Bossinger B, Strasser T, Janning W, Klapper R. 2003. The two origins of hemocytes in Drosophila. Development 130:4955-4962.
85. +/-mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors. J. Transl. Med. 8:14. doi:10.1186/1479 -5876-8-14.
86. Lee N, Woodrum CL, Nobil AM, Rauktys AE, Messina MP, Dabora SL. 2009. Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC Pharmacol. 9:8. doi: 10.1186/1471-2210-9-8.