Phosphoproteomic analysis implicates the mTORC2-FoxO1 axis in VEGF signaling and feedback activation of receptor tyrosine kinases

Science Signaling

Volumn 6, Issue 271, 2013, Pages

  Zhuang, Guanglei ^a   Yu, Kebing ^a   Jiang, Zhaoshi ^a   Chung, Alicia ^a   Yao, Jenny ^a   Ha, Connie ^a   Toy, Karen ^a   Soriano, Robert ^a   Haley, Benjamin ^a   Blackwood, Elizabeth ^a   Sampath, Deepak ^a   Bais, Carlos ^a   Lill, Jennie R ^a   Ferrara, Napoleone ^a,b  

^a GENENTECH INC   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; AZD 8055; CYTOSKELETON PROTEIN; GNE 236; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHALLOIDIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHOPROTEIN; PHOSPHOPROTEIN PHOSPHATASE; PICTILISIB; PROTEIN TYROSINE KINASE; SELUMETINIB; SMALL INTERFERING RNA; SORAFENIB; TRANSCRIPTION FACTOR FKHR; UNCLASSIFIED DRUG; VASCULOTROPIN; VASCULOTROPIN RECEPTOR;

ACTIN FILAMENT; ANTIBODY AFFINITY; APOPTOSIS; ARTICLE; CELL ADHESION; CELL JUNCTION; CELL MOTILITY; CELL SURVIVAL; CELL VIABILITY; CELLS; CONTROLLED STUDY; ENDOTHELIUM CELL; ENZYME ACTIVATION; ENZYME INHIBITION; FEEDBACK SYSTEM; FOCAL ADHESION; GROWTH INHIBITION; HUMAN; HUMAN CELL; IMMUNOBLOTTING; IN VITRO STUDY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEOMICS; SIGNAL TRANSDUCTION; TUMOR VASCULARIZATION; UMBILICAL VEIN ENDOTHELIAL CELL; WESTERN BLOTTING;

APOPTOSIS; ENZYME ACTIVATION; FORKHEAD TRANSCRIPTION FACTORS; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; MULTIPROTEIN COMPLEXES; PHOSPHOPEPTIDES; PHOSPHORYLATION; PROTEOMICS; RECEPTOR PROTEIN-TYROSINE KINASES; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

MAMMALIA;

EID: 84876586696     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.2003572]     Document Type: Article

References (75)

1. A. S. Chung, N. Ferrara, Developmental and pathological angiogenesis. Annu. Rev. Cell Dev. Biol. 27, 563-584 (2011).
2. A. S. Chung, J. Lee, N. Ferrara, Targeting the tumour vasculature: Insights from physiological angiogenesis. Nat. Rev. Cancer 10, 505-514 (2010).
3. N. Ferrara, Binding to the extracellular matrix and proteolytic processing: Two key mechanisms regulating vascular endothelial growth factor action. Mol. Biol. Cell 21, 687-690 (2010).
4. N. Ferrara, H. P. Gerber, J. LeCouter, The biology of VEGF and its receptors. Nat. Med. 9, 669-676 (2003).
5. S. Koch, L. Claesson-Welsh, Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb. Perspect. Med. 2, a006502 (2012).
6. S. Soker, S. Takashima, H. Q. Miao, G. Neufeld, M. Klagsbrun, Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735-745 (1998).
7. G. Neufeld, T. Cohen, N. Shraga, T. Lange, O. Kessler, Y. Herzog, The neuropilins: Multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc. Med. 12, 13-19 (2002).
8. J. E. Park, H. H. Chen, J. Winer, K. A. Houck, N. Ferrara, Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J. Biol. Chem. 269, 25646-25654 (1994).
9. A. K. Olsson, A. Dimberg, J. Kreuger, L. Claesson-Welsh, VEGF receptor signaling - In control of vascular function. Nat. Rev. Mol. Cell Biol. 7, 359-371 (2006).
10. M. Shibuya, L. Claesson-Welsh, Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp. Cell Res. 312, 549-560 (2006).
11. T. Pawson, P. Nash, Assembly of cell regulatory systems through protein interaction domains. Science 300, 445-452 (2003).
12. J. Schlessinger, Cell signaling by receptor tyrosine kinases. Cell 103, 211-225 (2000).
13. P. Blume-Jensen, T. Hunter, Oncogenic kinase signalling. Nature 411, 355-365 (2001).
14. M. J. Cross, J. Dixelius, T. Matsumoto, L. Claesson-Welsh, VEGF-receptor signal transduction. Trends Biochem. Sci. 28, 488-494 (2003).
15. T. L. Yuan, H. S. Choi, A. Matsui, C. Benes, E. Lifshits, J. Luo, J. V. Frangioni, L. C. Cantley, Class 1A PI3K regulates vessel integrity during development and tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 105, 9739-9744 (2008).
16. C. R. Schnell, F. Stauffer, P. R. Allegrini, T. O'Reilly, P. M. McSheehy, C. Dartois, M. Stumm, R. Cozens, A. Littlewood-Evans, C. García- Echeverría, S. M. Maira, Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: Implications for clinical imaging. Cancer Res. 68, 6598-6607 (2008).
17. L. C. Kim, L. Song, E. B. Haura, Src kinases as therapeutic targets for cancer. Nat. Rev. Clin. Oncol. 6, 587-595 (2009).
18. A. Moritz, Y. Li, A. Guo, J. Villén, Y. Wang, J. MacNeill, J. Kornhauser, K. Sprott, J. Zhou, A. Possemato, J. M. Ren, P. Hornbeck, L. C. Cantley, S. P. Gygi, J. Rush, M. J. Comb, Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Sci. Signal. 3, ra64 (2010).
19. J. N. Andersen, S. Sathyanarayanan, A. Di Bacco, A. Chi, T. Zhang, A. H. Chen, B. Dolinski, M. Kraus, B. Roberts, W. Arthur, R. A. Klinghoffer, D. Gargano, L. Li, I. Feldman, B. Lynch, J. Rush, R. C. Hendrickson, P. Blume-Jensen, C. P. Paweletz, Pathway-based identification of biomarkers for targeted therapeutics: Personalized oncology with PI3K pathway inhibitors. Sci. Transl. Med. 2, 43ra55 (2010).
20. A. Thompson, J. Schäfer, K. Kuhn, S. Kienle, J. Schwarz, G. Schmidt, T. Neumann, R. Johnstone, A. K. Mohammed, C. Hamon, Tandem mass tags: A novel quantification strategy for comparative analysis of complex protein mixtures by MS/MS. Anal. Chem. 75, 1895-1904 (2003).
21. P. R. Kvietys, D. N. Granger, Endothelial cell monolayers as a tool for studying microvascular pathophysiology. Am. J. Physiol. 273, G1189-G1199 (1997).
22. R. Auerbach, N. Akhtar, R. L. Lewis, B. L. Shinners, Angiogenesis assays: Problems and pitfalls. Cancer Metastasis Rev. 19, 167-172 (2000).
23. A. M. Goodwin, In vitro assays of angiogenesis for assessment of angiogenic and anti-angiogenic agents. Microvasc. Res. 74, 172-183 (2007).
24. T. Takahashi, H. Ueno, M. Shibuya, VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18, 2221-2230 (1999).
25. T. H. Nguyen, L. Brechenmacher, J. T. Aldrich, T. R. Clauss, M. A. Gritsenko, K. K. Hixson, M. Libault, K. Tanaka, F. Yang, Q. Yao, L. Pasa-Tolić, D. Xu, H. T. Nguyen, G. Stacey, Quantitative phosphoproteomic analysis of soybean root hairs inoculated with Bradyrhizobium japonicum. Mol. Cell. Proteomics 11, 1140-1155 (2012).
26. Z. Li, R. M. Adams, K. Chourey, G. B. Hurst, R. L. Hettich, C. Pan, Systematic comparison of label-free, metabolic labeling, and isobaric chemical labeling for quantitative proteomics on LTQ Orbitrap Velos. J. Proteome Res. 11, 1582-1590 (2012).
27. J. V. Olsen, B. Blagoev, F. Gnad, B. Macek, C. Kumar, P. Mortensen, M. Mann, Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635-648 (2006).
28. M. E. Futschik, B. Carlisle, Noise-robust soft clustering of gene expression time-course data. J. Bioinform. Comput. Biol. 3, 965-988 (2005).
29. M. Oyama, T. Nagashima, T. Suzuki, H. Kozuka-Hata, N. Yumoto, Y. Shiraishi, K. Ikeda, Y. Kuroki, N. Gotoh, T. Ishida, S. Inoue, H. Kitano, M. Okada-Hatakeyama, Integrated quantitative analysis of the phosphoproteome and transcriptome in tamoxifen-resistant breast cancer. J. Biol. Chem. 286, 818-829 (2011).
30. A. Lachmann, A. Ma'ayan, KEA: Kinase enrichment analysis. Bioinformatics 25, 684-686 (2009).
31. R. Zoncu, A. Efeyan, D. M. Sabatini, mTOR: From growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21-35 (2011).
32. K. Hamada, T. Sasaki, P. A. Koni, M. Natsui, H. Kishimoto, J. Sasaki, N. Yajima, Y. Horie, G. Hasegawa, M. Naito, J. Miyazaki, T. Suda, H. Itoh, K. Nakao, T. W. Mak, T. Nakano, A. Suzuki, The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes Dev. 19, 2054-2065 (2005).
33. V. S. Rodrik-Outmezguine, S. Chandarlapaty, N. C. Pagano, P. I. Poulikakos, M. Scaltriti, E. Moskatel, J. Baselga, S. Guichard, N. Rosen, mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1, 248-259 (2011).
34. S. Chandarlapaty, A. Sawai, M. Scaltriti, V. Rodrik-Outmezguine, O. Grbovic-Huezo, V. Serra, P. K. Majumder, J. Baselga, N. Rosen, AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58-71 (2011).
35. N. Ferrara, K. Carver-Moore, H. Chen, M. Dowd, L. Lu, K. S. O'Shea, L. Powell-Braxton, K. J. Hillan, M. W. Moore, Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439-442 (1996).
36. P. Carmeliet, V. Ferreira, G. Breier, S. Pollefeyt, L. Kieckens, M. Gertsenstein, M. Fahrig, A. Vandenhoeck, K. Harpal, C. Eberhardt, C. Declercq, J. Pawling, L. Moons, D. Collen, W. Risau, A. Nagy, Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435-439 (1996).
37. M. Singh, N. Ferrara, Modeling and predicting clinical efficacy for drugs targeting the tumor milieu. Nat. Biotechnol. 30, 648-657 (2012).
38. L. S. Lim, P. Mitchell, J. M. Seddon, F. G. Holz, T. Y. Wong, Age-related macular degeneration. Lancet 379, 1728-1738 (2012).
39. J. Dancey, mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol. 7, 209-219 (2010).
40. B. T. Hennessy, D. L. Smith, P. T. Ram, Y. Lu, G. B. Mills, Exploiting the PI3K/ AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 4, 988-1004 (2005).
41. J. A. Engelman, Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat. Rev. Cancer 9, 550-562 (2009).
42. K. K. Wong, J. A. Engelman, L. C. Cantley, Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20, 87-90 (2010).
43. H. Gille, J. Kowalski, B. Li, J. LeCouter, B. Moffat, T. F. Zioncheck, N. Pelletier, N. Ferrara, Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J. Biol. Chem. 276, 3222-3230 (2001).
44. J. Waltenberger, L. Claesson-Welsh, A. Siegbahn, M. Shibuya, C. H. Heldin, Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J. Biol. Chem. 269, 26988-26995 (1994).
45. S. Hiratsuka, O. Minowa, J. Kuno, T. Noda, M. Shibuya, Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl. Acad. Sci. U.S.A. 95, 9349-9354 (1998).
46. J. Yao, X. Wu, G. Zhuang, I. M. Kasman, T. Vogt, V. Phan, M. Shibuya, N. Ferrara, C. Bais, Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti- PlGF antibodies efficacy. Proc. Natl. Acad. Sci. U.S.A. 108, 11590-11595 (2011).
47. B. Li, G. Fuh, G. Meng, X. Xin, M. E. Gerritsen, B. Cunningham, A. M. de Vos, Receptor-selective variants of human vascular endothelial growth factor. Generation and characterization. J. Biol. Chem. 275, 29823-29828 (2000).
48. J. LeCouter, D. R. Moritz, B. Li, G. L. Phillips, X. H. Liang, H. P. Gerber, K. J. Hillan, N. Ferrara, Angiogenesis-independent endothelial protection of liver: Role of VEGFR-1. Science 299, 890-893 (2003).
49. K. Hattori, B. Heissig, Y. Wu, S. Dias, R. Tejada, B. Ferris, D. J. Hicklin, Z. Zhu, P. Bohlen, L. Witte, J. Hendrikx, N. R. Hackett, R. G. Crystal, M. A. Moore, Z. Werb, D. Lyden, S. Rafii, Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment. Nat. Med. 8, 841-849 (2002).
50. M. Graupera, J. Guillermet-Guibert, L. C. Foukas, L. K. Phng, R. J. Cain, A. Salpekar, W. Pearce, S. Meek, J. Millan, P. R. Cutillas, A. J. Smith, A. J. Ridley, C. Ruhrberg, H. Gerhardt, B. Vanhaesebroeck, Angiogenesis selectively requires the p110a isoform of PI3K to control endothelial cell migration. Nature 453, 662-666 (2008).
51. D. A. Guertin, D. M. Stevens, C. C. Thoreen, A. A. Burds, N. Y. Kalaany, J. Moffat, M. Brown, K. J. Fitzgerald, D. M. Sabatini, Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCa, but not S6K1. Dev. Cell 11, 859-871 (2006).
52. T. Hosaka,W. H. Biggs III, D. Tieu, A. D. Boyer, N. M. Varki, W. K. Cavenee, K. C. Arden, Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc. Natl. Acad. Sci. U.S.A. 101, 2975-2980 (2004).
53. T. Furuyama, K. Kitayama, Y. Shimoda, M. Ogawa, K. Sone, K. Yoshida-Araki, H. Hisatsune, S. Nishikawa, K. Nakayama, K. Nakayama, K. Ikeda, N. Motoyama, N. Mori, Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J. Biol. Chem. 279, 34741-34749 (2004).
54. E. Jacinto, V. Facchinetti, D. Liu, N. Soto, S. Wei, S. Y. Jung, Q. Huang, J. Qin, B. Su, SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125-137 (2006).
55. J. H. Paik, R. Kollipara, G. Chu, H. Ji, Y. Xiao, Z. Ding, L. Miao, Z. Tothova, J. W. Horner, D. R. Carrasco, S. Jiang, D. G. Gilliland, L. Chin, W. H. Wong, D. H. Castrillon, R. A. DePinho, FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309-323 (2007).
56. P. F. Dijkers, R. H. Medema, J. W. Lammers, L. Koenderman, P. J. Coffer, Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol. 10, 1201-1204 (2000).
57. Y. Sakurai, K. Ohgimoto, Y. Kataoka, N. Yoshida, M. Shibuya, Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc. Natl. Acad. Sci. U.S.A. 102, 1076-1081 (2005).
58. T. Takahashi, S. Yamaguchi, K. Chida, M. Shibuya, A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-g and DNA synthesis in vascular endothelial cells. EMBO J. 20, 2768-2778 (2001).
59. K. Holmqvist, M. J. Cross, C. Rolny, R. Hägerkvist, N. Rahimi, T. Matsumoto, L. Claesson-Welsh, M. Welsh, The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. J. Biol. Chem. 279, 22267-22275 (2004).
60. S. Chandarlapaty, Negative feedback and adaptive resistance to the targeted therapy of cancer. Cancer Discov. 2, 311-319 (2012).
61. D. P. Sutherlin, L. Bao, M. Berry, G. Castanedo, I. Chuckowree, J. Dotson, A. Folks, L. Friedman, R. Goldsmith, J. Gunzner, T. Heffron, J. Lesnick, C. Lewis, S. Mathieu, J. Murray, J. Nonomiya, J. Pang, N. Pegg, W.W. Prior, L. Rouge, L. Salphati, D. Sampath, Q. Tian, V. Tsui,N. C. Wan, S.Wang, B. Wei,C. Wiesmann, P. Wu, B. Y. Zhu, A. Olivero, Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J. Med. Chem. 54, 7579-7587 (2011).
62. A. J. Folkes, K. Ahmadi, W. K. Alderton, S. Alix, S. J. Baker, G. Box, I. S. Chuckowree, P. A. Clarke, P. Depledge, S. A. Eccles, L. S. Friedman, A. Hayes, T. C. Hancox, A. Kugendradas, L. Lensun, P. Moore, A. G. Olivero, J. Pang, S. Patel, G. H. Pergl-Wilson, F. I. Raynaud, A. Robson, N. Saghir, L. Salphati, S. Sohal, M. H. Ultsch, M. Valenti, H. J. Wallweber, N. C. Wan, C. Wiesmann, P. Workman, A. Zhyvoloup, M. J. Zvelebil, S. J. Shuttleworth, The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin- 1-ylmethyl)-4-morpholin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem. 51, 5522-5532 (2008).
63. F. Cohen, P. Bergeron, E. Blackwood, K. K. Bowman, H. Chen, A. G. Dipasquale, J. A. Epler, M. F. Koehler, K. Lau, C. Lewis, L. Liu, C. Q. Ly, S. Malek, J. Nonomiya, D. F. Ortwine, Z. Pei, K. D. Robarge, S. Sideris, L. Trinh, T. Truong, J. Wu, X. Zhao, J. P. Lyssikatos, Potent, selective, and orally bioavailable inhibitors of mammalian target of rapamycin (mTOR) kinase based on a quaternary substituted dihydrofuropyrimidine. J. Med. Chem. 54, 3426-3435 (2011).
64. K. Lin, J. Lin, W. I. Wu, J. Ballard, B. B. Lee, S. L. Gloor, G. P. Vigers, T. H. Morales, L. S. Friedman, N. Skelton, B. J. Brandhuber, An ATP-site on-off switch that restricts phosphatase accessibility of Akt. Sci. Signal. 5, ra37 (2012).
65. J. Rush, A. Moritz, K. A. Lee, A. Guo, V. L. Goss, E. J. Spek, H. Zhang, X. M. Zha, R. D. Polakiewicz, M. J. Comb, Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat. Biotechnol. 23, 94-101 (2005).
66. M. R. Larsen, T. E. Thingholm, O. N. Jensen, P. Roepstorff, T. J. Jørgensen, Highly selective enrichment of phosphorylated peptides from peptide mixtures using titanium dioxide microcolumns. Mol. Cell. Proteomics 4, 873-886 (2005).
67. E. L. Huttlin, M. P. Jedrychowski, J. E. Elias, T. Goswami, R. Rad, S. A. Beausoleil, J. Villen, W. Haas, M. E. Sowa, S. P. Gygi, A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143, 1174-1189 (2010).
68. S. A. Beausoleil, J. Villén, S. A. Gerber, J. Rush, S. P. Gygi, A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat. Biotechnol. 24, 1285-1292 (2006).
69. L. Dayon, A. Hainard, V. Licker, N. Turck, K. Kuhn, D. F. Hochstrasser, P. R. Burkhard, J. C. Sanchez, Relative quantification of proteins in human cerebrospinal fluids by MS/MS using 6-plex isobaric tags. Anal. Chem. 80, 2921-2931 (2008).
70. R. A. Irizarry, B. Hobbs, F. Collin, Y. D. Beazer-Barclay, K. J. Antonellis, U. Scherf, T. P. Speed, Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249-264 (2003).
71. G. K. Smyth, Y. H. Yang, T. Speed, Statistical issues in cDNA microarray data analysis. Methods Mol. Biol. 224, 111-136 (2003).
72. G. Zhuang, X. Wu, Z. Jiang, I. Kasman, J. Yao, Y. Guan, J. Oeh, Z. Modrusan, C. Bais, D. Sampath, N. Ferrara, Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J. 31, 3513-3523 (2012).
73. K. T. Rigbolt, J. T. Vanselow, B. Blagoev, GProX, a user-friendly platform for bioinformatics analysis and visualization of quantitative proteomics data. Mol. Cell. Proteomics 10, O110.007450 (2011).
74. D. W. Huang, B. T. Sherman, R. A. Lempicki, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44-57 (2009).
75. D. W. Huang, B. T. Sherman, R. A. Lempicki, Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1-13 (2009).