Raf kinases in cancer-roles and therapeutic opportunities

Oncogene

Volumn 30, Issue 32, 2011, Pages 3477-3488

  Maurer, G ^a   Tarkowski, B ^a   Baccarini, M ^a  

^a UNIVERSITY OF VIENNA   (Austria)

Author keywords

ERK pathway; hallmarks of cancer; kinase inhibitors; Raf; Ras

Indexed keywords

B RAF KINASE; B RAF KINASE INHIBITOR; CELL CYCLE PROTEIN 37; FIBROBLAST GROWTH FACTOR 1; GAG PROTEIN; GELATINASE B; GSK 2118436; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; IMATINIB; LEUKOCYTE ANTIGEN; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHODIESTERASE V; PROTEIN BCL 2; PROTEIN P15; PROTEIN P53; RAF PROTEIN; RETINOBLASTOMA PROTEIN; SMAD4 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; TUMOR MARKER; UNCLASSIFIED DRUG; VASCULOTROPIN; VEMURAFENIB; VOLTAGE DEPENDENT ANION CHANNEL;

ANGIOGENESIS; APOPTOSIS; BLADDER CANCER; CANCER CHEMOTHERAPY; CANCER GROWTH; CANCER SURVIVAL; CARCINOGENESIS; CELL PROLIFERATION; CELL TRANSFORMATION; CHROMOSOMAL INSTABILITY; CHROMOSOME REARRANGEMENT; CLINICAL FEATURE; COLON CANCER; DNA REPLICATION; DRUG EFFICACY; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INHIBITION; GENOMIC INSTABILITY; HEAD AND NECK CANCER; HUMAN; IMMUNOSURVEILLANCE; LIVER CELL CARCINOMA; LUNG ADENOCARCINOMA; MELANOMA; MELANOMA CELL; METASTASIS; NEGATIVE FEEDBACK; NONHUMAN; ONCOGENE RAS; OXIDATIVE STRESS; PILOCYTIC ASTROCYTOMA; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW; SENESCENCE; SQUAMOUS CELL CARCINOMA; STOMACH CANCER; THYROID CANCER; THYROID CARCINOMA; TREATMENT RESPONSE; TUMOR GENE; TUMOR XENOGRAFT;

ENZYME ACTIVATION; HUMANS; INDOLES; MAP KINASE SIGNALING SYSTEM; MODELS, BIOLOGICAL; NEOPLASMS; PROTO-ONCOGENE PROTEINS B-RAF; PROTO-ONCOGENE PROTEINS C-RAF; RAS PROTEINS; SULFONAMIDES;

MAMMALIA;

EID: 80051802020     PISSN: 09509232     EISSN: 14765594     Source Type: Journal    
DOI: 10.1038/onc.2011.160     Document Type: Review

References (149)

1. Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA. (2003). Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301:94-96. (Pubitemid 36801568)
2. Alavi AS, Acevedo L, Min W, Cheresh DA. (2007). Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res 67:2766-2772. (Pubitemid 46548965)
3. Argast GM, Croy CH, Couts KL, Zhang Z, Litman E, Chan DC et al. (2009). Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells. Oncogene 28:2697-2709.
4. Arkenau HT, Kefford R, Long GV. (2010). Targeting BRAF for patients with melanoma. Br J Cancer 104:392-398.
5. Arozarena I, Sanchez-Laorden B, Packer L, Hidalgo-Carcedo C, Hayward R, Viros A et al. (2010). Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A. Cancer Cell 19:45-57.
6. Balmanno K, Cook SJ. (2009). Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ 16:368-377.
7. Baumann B, Weber CK, Troppmair J, Whiteside S, Israel A, Rapp UR et al. (2000). Raf induces NF-kappa B by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Proc Natl Acad Sci USA 97:4615-4620. (Pubitemid 30238606)
8. Beliveau A, Mott JD, Lo A, Chen EI, Koller AA, Yaswen P et al. (2010). Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo. Genes Dev 24:2800-2811.
9. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H et al. (2010). Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596-599.
10. Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN, Sloss CM et al. (2010). Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 70:5213-5219.
11. Calipel A, Mouriaux F, Glotin AL, Malecaze F, Faussat AM, Mascarelli F. (2006). Extracellular signal-regulated kinase-dependent proliferation is mediated through the protein kinase A/B-Raf pathway in human uveal melanoma cells. J Biol Chem 281:9238-9250. (Pubitemid 43864639)
12. Carragher LA, Snell KR, Giblett SM, Aldridge VS, Patel B, Cook SJ et al. (2010). V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a. EMBO Mol Med 2:458-471.
13. Catalanotti F, Reyes G, Jesenberger V, Galabova-Kovacs G, de Matos Simoes R, Carugo O et al. (2009). A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nat Struct Mol Biol 16:294-303.
14. Cekanova M, Majidy M, Masi T, Al-Wadei HA, Schuller HM. (2007). Overexpressed Raf-1 and phosphorylated cyclic adenosine 30-50-monophosphatate response element-binding protein are early markers for lung adenocarcinoma. Cancer 109:1164-1173. (Pubitemid 46435397)
15. Ceteci F, Ceteci S, Karreman C, Kramer BW, Asan E, Gotz R et al. (2007). Disruption of tumor cell adhesion promotes angiogenic switch and progression to micrometastasis in RAF-driven murine lung cancer. Cancer Cell 12:145-159. (Pubitemid 47199121)
16. Chan SR, Blackburn EH. (2004). Telomeres and telomerase. Philos Trans R Soc Lond B Biol Sci 359:109-121. (Pubitemid 38106454)
17. Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH et al. (2011). EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell 19:86-100.
18. Chen J, Fujii K, Zhang L, Roberts T, Fu H. (2001). Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci USA 98:7783-7788. (Pubitemid 32642638)
19. Cheung M, Sharma A, Madhunapantula SV, Robertson GP. (2008). Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. Cancer Res 68:3429-3439.
20. Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN et al. (2005). Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 115:94-101. (Pubitemid 40385509)
21. Dai Y, Chen S, Pei XY, Almenara JA, Kramer LB, Venditti CA et al. (2008). Interruption of the Ras/MEK/ERK signaling cascade enhances Chk1 inhibitor-induced DNA damage in vitro and in vivo in human multiple myeloma cells. Blood 112:2439-2449.
22. Dangi-Garimella S, Yun J, Eves EM, Newman M, Erkeland SJ, Hammond SM et al. (2009). Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J 28:347-358.
23. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky Jr WE et al. (2009). Braf (V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41:544-552.
24. Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M. (2007). A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev 21:379-384.
25. Dasgupta P, Rastogi S, Pillai S, Ordonez-Ercan D, Morris M, Haura E et al. (2006). Nicotine induces cell proliferation by beta-arrestinmediated activation of Src and Rb-Raf-1 pathways. J Clin Invest 116:2208-2217. (Pubitemid 44162330)
26. Dasgupta P, Sun J, Wang S, Fusaro G, Betts V, Padmanabhan J et al. (2004). Disruption of the Rb-Raf-1 interaction inhibits tumor growth and angiogenesis. Mol Cell Biol 24:9527-9541. (Pubitemid 39391689)
27. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al. (2002). Mutations of the BRAF gene in human cancer. Nature 417:949-954. (Pubitemid 34716871)
28. Degen A, Satzger I, Voelker B, Kapp A, Hauschild A, Gutzmer R. (2010). Does basal cell carcinoma belong to the spectrum of sorafenib-induced epithelial skin cancers. Dermatology 221:193-196.
29. Dessars B, De Raeve LE, El Housni H, Debouck CJ, Sidon PJ, Morandini R et al. (2007). Chromosomal translocations as a mechanism of BRAF activation in two cases of large congenital melanocytic nevi. J Invest Dermatol 127:1468-1470. (Pubitemid 46762984)
30. Dhomen N, Reis-Filho JS, Da Rocha Dias S, Hayward R, Savage K, Delmas V et al. (2009). Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15:294-303.
31. Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD et al. (2005). Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17:215-224. (Pubitemid 40138617)
32. Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin JA et al. (2006). In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res 66:9483-9491. (Pubitemid 44623646)
33. Dunn GP, Old LJ, Schreiber RD. (2004). The three Es of cancer immunoediting. Annu Rev Immunol 22:329-360. (Pubitemid 38680426)
34. Dwyer J, Li H, Xu D, Liu JP. (2007). Transcriptional regulation of telomerase activity: roles of the Ets transcription factor family. Ann NY Acad Sci 1114:36-47. (Pubitemid 350070389)
35. Edwards J, Krishna NS, Witton CJ, Bartlett JM. (2003). Gene amplifications associated with the development of hormoneresistant prostate cancer. Clin Cancer Res 9:5271-5281. (Pubitemid 37413579)
36. Ehrenreiter K, Kern F, Velamoor V, Meissl K, Galabova-Kovacs G, Sibilia M et al. (2009). Raf-1 addiction in Ras-induced skin carcinogenesis. Cancer Cell 16:149-160.
37. Ehrenreiter K, Piazzolla D, Velamoor V, Sobczak I, Small JV, Takeda J et al. (2005). Raf-1 regulates Rho signaling and cell migration. J Cell Biol 168:955-964. (Pubitemid 40397009)
38. Emuss V, Garnett M, Mason C, Marais R. (2005). Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res 65:9719-9726. (Pubitemid 41541448)
39. Eves EM, Shapiro P, Naik K, Klein UR, Trakul N, Rosner MR. (2006). Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell 23:561-574. (Pubitemid 44205493)
40. Fan S, Meng Q, Laterra JJ, Rosen EM. (2007). Ras effector pathways modulate scatter factor-stimulated NF-(kappa) B signaling and protection against DNA damage. Oncogene 26:4774-4796. (Pubitemid 47093168)
41. Fedorov LM, Papadopoulos T, Tyrsin OY, Twardzik T, Gotz R, Rapp UR. (2003). Loss of p53 in craf-induced transgenic lung adenoma leads to tumor acceleration and phenotypic switch. Cancer Res 63:2268-2277. (Pubitemid 36538636)
42. Fedorov LM, Tyrsin OY, Papadopoulos T, Camarero G, Gotz R, Rapp UR. (2002). Bcl-2 determines susceptibility to induction of lung cancer by oncogenic CRaf. Cancer Res 62:6297-6303. (Pubitemid 35244484)
43. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA et al. (2010). Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809-819.
44. Fukuyo Y, Inoue M, Nakajima T, Higashikubo R, Horikoshi NT, Hunt C et al. (2008). Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives. Cancer Res 68:6324-6330.
45. Garnett MJ, Rana S, Paterson H, Barford D, Marais R. (2005). Wildtype and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell 20:963-969. (Pubitemid 41814884)
46. Goel VK, Ibrahim N, Jiang G, Singhal M, Fee S, Flotte T et al. (2009). Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice. Oncogene 28:2289-2298.
47. Goel VK, Lazar AJ, Warneke CL, Redston MS, Haluska FG. (2006). Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol 126:154-160. (Pubitemid 43336107)
48. Golding SE, Rosenberg E, Neill S, Dent P, Povirk LF, Valerie K. (2007). Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res 67:1046-1053.
49. Goueli BS, Janknecht R. (2004). Upregulation of the catalytic telomerase subunit by the transcription factor ER81 and oncogenic HER2/Neu, Ras, or Raf. Mol Cell Biol 24:25-35. (Pubitemid 38010032)
50. Granovsky AE, Rosner MR. (2008). Raf kinase inhibitory protein: a signal transduction modulator and metastasis suppressor. Cell Res 18:452-457. (Pubitemid 351498852)
51. Gray-Schopfer VC, Cheong SC, Chong H, Chow J, Moss T, Abdel-Malek ZA et al. (2006). Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer 95:496-505. (Pubitemid 44232559)
52. Han JA, Kim JI, Ongusaha PP, Hwang DH, Ballou LR, Mahale A et al. (2002). p53-mediated induction of Cox-2 counteracts p53-or genotoxic stress-induced apoptosis. EMBO J 21:5635-5644. (Pubitemid 35315263)
53. Hanahan D, Weinberg RA. (2000). The hallmarks of cancer. Cell 100:57-70. (Pubitemid 30046295)
54. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R et al. (2010). RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464:431-435.
55. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N et al. (2010). Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140:209-221.
56. Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R et al. (2002). Tumor regression by targeted gene delivery to the neovasculature. Science 296:2404-2407. (Pubitemid 34734217)
57. Hwang YH, Choi JY, Kim S, Chung ES, Kim T, Koh SS et al. (2004). Overexpression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol Res 29:113-121. (Pubitemid 38667508)
58. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J et al. (2002). Ras and TGF (beta) cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156:299-313. (Pubitemid 34839911)
59. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA et al. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968-972.
60. Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K et al. (2008). Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673-8677.
61. Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP. (2009). Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28:2119-2123.
62. Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS et al. (2010). The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci USA 107:14903-14908.
63. Kamata T, Hussain J, Giblett S, Hayward R, Marais R, Pritchard C. (2010). BRAF inactivation drives aneuploidy by deregulating CRAF. Cancer Res 70:8475-8486.
64. Karreth FA, DeNicola GM, Winter SP, Tuveson DA. (2009). C-Raf inhibits MAPK activation and transformation by B-RafV600E. Mol Cell 36:477-486.
65. Kasid U, Pfeifer A, Brennan T, Beckett M, Weichselbaum RR, Dritschilo A et al. (1989). Effect of antisense c-raf-1 on tumorigenicity and radiation sensitivity of a human squamous carcinoma. Science 243:1354-1356. (Pubitemid 19085371)
66. Kasid U, Pfeifer A, Weichselbaum RR, Dritschilo A, Mark GE. (1987). The raf oncogene is associated with a radiation-resistant human laryngeal cancer. Science 237:1039-1041. (Pubitemid 17131202)
67. Kasid U, Suy S, Dent P, Ray S, Whiteside TL, Sturgill TW. (1996). Activation of Raf by ionizing radiation. Nature 382:813-816. (Pubitemid 26299565)
68. Kefford R, Arkenau H, Brown MP, Millward M, Infante JR, Long GV et al. (2010). Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. ASCO Meeting Abstracts 28:8503.
69. Kerkhoff E, Fedorov LM, Siefken R, Walter AO, Papadopoulos T, Rapp UR. (2000). Lung-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel oncogenic character of the wild-type protein. Cell Growth Differ 11:185-190. (Pubitemid 30211007)
70. Kessenbrock K, Plaks V, Werb Z. (2010). Matrix metalloproteinases: regulators of the Tumor Microenvironment. Cell 141:52-67.
71. Kinkade R, Dasgupta P, Carie A, Pernazza D, Carless M, Pillai S et al. (2008). A small molecule disruptor of Rb/Raf-1 interaction inhibits cell proliferation, angiogenesis, and growth of human tumor xenografts in nude mice. Cancer Res 68:3810-3818.
72. Klein RM, Spofford LS, Abel EV, Ortiz A, Aplin AE. (2008). B-RAF regulation of Rnd3 participates in actin cytoskeletal and focal adhesion organization. Mol Biol Cell 19:498-508. (Pubitemid 351272139)
73. Kolch W. (2005). Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6:827-837. (Pubitemid 41568732)
74. Kramer BW, Gotz R, Rapp UR. (2004). Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure. BMC Cancer 4:24.
75. Kroemer G, Pouyssegur J. (2008). Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 13:472-482. (Pubitemid 351766797)
76. Kumar SM, Yu H, Edwards R, Chen L, Kazianis S, Brafford P et al. (2007). Mutant V600E BRAF increases hypoxia inducible factor-1alpha expression in melanoma. Cancer Res 67:3177-3184. (Pubitemid 46724855)
77. Kuznetsov AV, Smigelskaite J, Doblander C, Janakiraman M, Hermann M, Wurm M et al. (2008). Survival signaling by C-RAF: mitochondrial reactive oxygen species and Ca2+ are critical targets. Mol Cell Biol 28:2304-2313. (Pubitemid 351429976)
78. Lehmann K, Janda E, Pierreux CE, Rytomaa M, Schulze A, McMahon M et al. (2000). Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 14:2610-2622.
79. Liang S, Sharma A, Peng HH, Robertson G, Dong C. (2007). Targeting mutant (V600E) B-Raf in melanoma interrupts immunoediting of leukocyte functions and melanoma extravasation. Cancer Res 67:5814-5820. (Pubitemid 46985015)
80. Luo J, Solimini NL, Elledge SJ. (2009). Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823-837.
81. Lyustikman Y, Momota H, Pao W, Holland EC. (2008). Constitutive activation of Raf-1 induces glioma formation in mice. Neoplasia 10:501-510. (Pubitemid 351657392)
82. Marx M, Eychene A, Laugier D, Bechade C, Crisanti P, Dezelee P et al. (1988). A novel oncogene related to c-mil is transduced in chicken neuroretina cells induced to proliferate by infection with an avian lymphomatosis virus. EMBO J 7:3369-3373.
83. Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Piazzolla D et al. (2007). RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol Cell 27:962-975. (Pubitemid 47495894)
84. Matos P, Oliveira C, Velho S, Goncalves V, da Costa LT, Moyer MP et al. (2008). B-Raf (V600E) cooperates with alternative spliced Rac1b to sustain colorectal cancer cell survival. Gastroenterology 135:899-906.
85. McKay MM, Morrison DK. (2007). Integrating signals from RTKs to ERK/MAPK. Oncogene 26:3113-3121. (Pubitemid 46763008)
86. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM et al. (2005). BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720-724. (Pubitemid 41117276)
87. Mitsutake N, Knauf JA, Mitsutake S, Mesa Jr C, Zhang L, Fagin JA. (2005). Conditional BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal instability in thyroid PCCL3 cells. Cancer Res 65:2465-2473. (Pubitemid 40490159)
88. Moelling K, Heimann B, Beimling P, Rapp UR, Sander T. (1984). Serine-and threonine-specific protein kinase activities of purified gag-mil and gag-raf proteins. Nature 312:558-561. (Pubitemid 15182287)
89. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H et al. (2010). Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973-977.
90. Negrini S, Gorgoulis VG, Halazonetis TD. (2010). Genomic instability-an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11:220-228.
91. Niault TS, Baccarini M. (2010). Targets of Raf in tumorigenesis. Carcinogenesis 31:1165-1174.
92. O'Neill E, Rushworth L, Baccarini M, Kolch W. (2004). Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 306:2267-2270. (Pubitemid 40024466)
93. Old WM, Shabb JB, Houel S, Wang H, Couts KL, Yen CY et al. (2009). Functional proteomics identifies targets of phosphorylation by B-Raf signaling in melanoma. Mol Cell 34:115-131.
94. Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K, Shankar S et al. (2010). Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16:793-798.
95. Park BJ, Park JI, Byun DS, Park JH, Chi SG. (2000). Mitogenic conversion of transforming growth factor-beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer. Cancer Res 60:3031-3038.
96. Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N et al. (2008). BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118:1739-1749. (Pubitemid 351632377)
97. Piazzolla D, Meissl K, Kucerova L, Rubiolo C, Baccarini M. (2005). Raf-1 sets the threshold of Fas sensitivity by modulating Rok-{alpha} signaling. J Cell Biol 171:1013-1022. (Pubitemid 41815833)
98. Polzien L, Baljuls A, Rennefahrt UE, Fischer A, Schmitz W, Zahedi RP et al. (2009). Identification of novel in vivo phosphorylation sites of the human proapoptotic protein BAD: pore-forming activity of BAD is regulated by phosphorylation. J Biol Chem 284:28004-28020.
99. Poulikakos PI, Rosen N. (2011). Mutant BRAF melanomas-dependence and resistance. Cancer Cell 19:11-15.
100. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. (2010). RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427-430.
101. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB et al. (2009). (V600E) BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci USA 106:4519-4524.
102. Pritchard CA, Hayes L, Wojnowski L, Zimmer A, Marais RM, Norman JC. (2004). B-Raf acts via the ROCKII/LIMK/cofilin pathway to maintain actin stress fibers in fibroblasts. Mol Cell Biol 24:5937-5952. (Pubitemid 38787977)
103. Pritchard CA, Samuels ML, Bosch E, McMahon M. (1995). Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells. Mol Cell Biol 15:6430-6442.
104. Puzanov I, Burnett P, Flaherty KT. (2011). Biological challenges of BRAF inhibitor therapy. Mol Oncol 5:116-123.
105. Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. (2009). A dimerization-dependent mechanism drives RAF catalytic activation. Nature 461:542-545.
106. Rapp UR, Goldsborough MD, Mark GE, Bonner TI, Groffen J, Reynolds Jr FH et al. (1983). Structure and biological activity of vraf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci USA 80:4218-4222. (Pubitemid 13077808)
107. Ravi RK, Weber E, McMahon M, Williams JR, Baylin S, Mal A et al. (1998). Activated Raf-1 causes growth arrest in human small cell lung cancer cells. J Clin Invest 101:153-159. (Pubitemid 28058914)
108. Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T et al. (2000). Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 103:321-330.
109. Riesco-Eizaguirre G, Rodriguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M et al. (2009). The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res 69:8317-8325.
110. Ritt DA, Monson DM, Specht SI, Morrison DK. (2010). Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling. Mol Cell Biol 30:806-819.
111. Riva C, Lavieille JP, Reyt E, Brambilla E, Lunardi J, Brambilla C. (1995). Differential c-myc, c-jun, c-raf and p53 expression in squamous cell carcinoma of the head and neck: implication in drug and radioresistance. Eur J Cancer B Oral Oncol 31:384-391. (Pubitemid 26009168)
112. Robert C, Arnault JP, Mateus C. (2010). RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr Opin Oncol 23:177-182.
113. Roper E, Weinberg W, Watt FM, Land H. (2001). p19ARF-independent induction of p53 and cell cycle arrest by Raf in murine keratinocytes. EMBO Rep 2:145-150. (Pubitemid 32229742)
114. Rushworth LK, Hindley AD, O'Neill E, Kolch W. (2006). Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol 26:2262-2272. (Pubitemid 43346926)
115. Sahai E, Marshall CJ. (2003). Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol 5:711-719. (Pubitemid 36986778)
116. Schulze A, Lehmann K, Jefferies HB, McMahon M, Downward J. (2001). Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev 15:981-994. (Pubitemid 32323548)
117. Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J. (2004). The transcriptional response to raf activation is almost completely dependent on mitogen-activated protein kinase kinase activity and shows a major autocrine component. Mol Biol Cell 15:3450-3463. (Pubitemid 38850136)
118. Seoane J. (2008). The TGFBeta pathway as a therapeutic target in cancer. Clin Transl Oncol 10:14-19.
119. Sewing A, Wiseman B, Lloyd AC, Land H. (1997). High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol 17:5588-5597. (Pubitemid 27357655)
120. Sharma A, Tran MA, Liang S, Sharma AK, Amin S, Smith CD et al. (2006). Targeting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in the mutant (V600E) B-Raf signaling cascade effectively inhibits melanoma lung metastases. Cancer Res 66:8200-8209. (Pubitemid 44299188)
121. Sharma A, Trivedi NR, Zimmerman MA, Tuveson DA, Smith CD, Robertson GP. (2005). Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res 65:2412-2421. (Pubitemid 40490153)
122. Shimizu K, Nakatsu Y, Nomoto S, Sekiguchi M. (1986). Structure of the activated c-raf-1 gene from human stomach cancer. Princess Takamatsu Symp 17:85-91.
123. Simon R, Richter J, Wagner U, Fijan A, Bruderer J, Schmid U et al. (2001). High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. Cancer Res 61:4514-4519. (Pubitemid 32685782)
124. Smyth MJ, Dunn GP, Schreiber RD. (2006). Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90:1-50. (Pubitemid 43765795)
125. Sobczak I, Galabova-Kovacs G, Sadzak I, Kren A, Christofori G, Baccarini M. (2008). B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic beta-cell carcinogenesis. Oncogene 27:4779-4787.
126. Sumimoto H, Imabayashi F, Iwata T, Kawakami Y. (2006). The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 203:1651-1656. (Pubitemid 44036269)
127. Takezawa K, Okamoto I, Yonesaka K, Hatashita E, Yamada Y, Fukuoka M et al. (2009). Sorafenib inhibits non-small cell lung cancer cell growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells. Cancer Res 69:6515-6521.
128. Tidyman WE, Rauen KA. (2009). The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19:230-236.
129. Troppmair J, Hartkamp J, Rapp UR. (1998). Activation of NF-kappa B by oncogenic Raf in HEK 293 cells occurs through autocrine recruitment of the stress kinase cascade. Oncogene 17:685-690. (Pubitemid 28412488)
130. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S et al. (2008). Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 105:3041-3046. (Pubitemid 351723664)
131. Vale T, Ngo TT, White MA, Lipsky PE. (2001). Raf-induced transformation requires an interleukin 1 autocrine loop. Cancer Res 61:602-607. (Pubitemid 32128621)
132. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK et al. (2010). Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683-695.
133. Wang S, Ghosh RN, Chellappan SP. (1998). Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation. Mol Cell Biol 18:7487-7498. (Pubitemid 28533067)
134. Wang X, Thomson SR, Starkey JD, Page JL, Ealy AD, Johnson SE. (2004). Transforming growth factor {beta}1 is upregulated by activated Raf in skeletal myoblasts but does not contribute to the differentiation-defective phenotype. J Biol Chem 279:2528-2534. (Pubitemid 38114237)
135. Wang ZY, Chen Z. (2008). Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111:2505-2515.
136. Weber CK, Slupsky JR, Kalmes HA, Rapp UR. (2001). Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res 61:3595-3598. (Pubitemid 32694968)
137. Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. (2007). Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7:345-356. (Pubitemid 46652483)
138. Wellbrock C, Karasarides M, Marais R. (2004). The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5:875-885. (Pubitemid 39486539)
139. Wimmer R, Baccarini M. (2010). Partner exchange: protein-protein interactions in the Raf pathway. Trends Biochem Sci 35:660-668.
140. Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M. (1997). Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol 17:5598-5611. (Pubitemid 27357656)
141. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ et al. (2007). RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447:864-868. (Pubitemid 46920135)
142. Yu H, McDaid R, Lee J, Possik P, Li L, Kumar SM et al. (2009). The role of BRAF mutation and p53 inactivation during transformation of a subpopulation of primary human melanocytes. Am J Pathol 174:2367-2377.
143. Zebisch A, Haller M, Hiden K, Goebel T, Hoefler G, Troppmair J et al. (2009). Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations. Leukemia 23:1049-1053.
144. Zebisch A, Staber PB, Delavar A, Bodner C, Hiden K, Fischereder K et al. (2006). Two transforming C-RAF germline mutations identified in patients with therapy-related acute myeloid leukemia. Cancer Res 66:3401-3408.
145. Zeng L, Imamoto A, Rosner MR. (2008). Raf kinase inhibitory protein (RKIP): a physiological regulator and future therapeutic target. Expert Opin Ther Targets 12:1275-1287.
146. Zheng B, Jeong JH, Asara JM, Yuan Y-Y, Granter SR, Chin L et al. (2009). Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 33:237-247.
147. Zhu J, Woods D, McMahon M, Bishop JM. (1998). Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 12:2997-3007. (Pubitemid 28469302)
148. Zhuang D, Mannava S, Grachtchouk V, Tang WH, Patil S, Wawrzyniak JA et al. (2008). C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells. Oncogene 27:6623-6634.
149. Zitvogel L, Tesniere A, Kroemer G. (2006). Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 6:715-727. (Pubitemid 44453458)