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Gene Review

BRAF  -  B-Raf proto-oncogene, serine/threonine kinase

Homo sapiens

Synonyms: B-RAF1, BRAF1, NS7, RAFB1
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Disease relevance of BRAF


High impact information on BRAF


Chemical compound and disease context of BRAF


Biological context of BRAF


Anatomical context of BRAF


Associations of BRAF with chemical compounds

  • Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro [23].
  • This effect occurs due to a specific TNF-alpha and BRAF interaction because TNF-alpha does not prevent cell death in the presence of cisplatin, nitrogen mustard or thapsigargin [24].
  • BRAF is a serine/threonine kinase that receives a mitogenic signal from RAS and transmits it to the MAP kinase pathway [25].
  • By combining expression profiles with mutational status, we defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups [26].
  • We detected one 1796 T-->A BRAF mutation that led to a substitution of valine by glutamic acid at position 599 (V599E) in 40 primary neuroendocrine GEP tumors (3%) [27].
  • BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism [28].

Regulatory relationships of BRAF


Other interactions of BRAF

  • Specifically, we found that oncogenic forms of HRAS (HRAS(G12V)) but not its downstream target BRAF (BRAF(V600E)), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER [34].
  • However, CIMP-high unstable tumors were significantly more likely than their stable counterparts to be KRAS2 wild type, TP53 wild type, poorly differentiated, proximally located, occur at lower stages, and have the BRAF V600E mutation (64.1% vs 17.6%) [35].
  • These results suggest a relationship of synthetic lethality between NRAS and BRAF oncogenes, leading to selection against "double-mutant" cells [36].
  • Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend the potential options for therapeutic targeting of kinases in the treatment of phenotypically distinct pancreatic adenocarcinoma subsets [37].
  • In order to further support this hypothesis, we have extended the analysis of the BRAF gene to a different subset of HNPCC families without germline mutations in MLH1 and MSH2 [38].

Analytical, diagnostic and therapeutic context of BRAF


  1. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Rajagopalan, H., Bardelli, A., Lengauer, C., Kinzler, K.W., Vogelstein, B., Velculescu, V.E. Nature (2002) [Pubmed]
  2. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. Ciampi, R., Knauf, J.A., Kerler, R., Gandhi, M., Zhu, Z., Nikiforova, M.N., Rabes, H.M., Fagin, J.A., Nikiforov, Y.E. J. Clin. Invest. (2005) [Pubmed]
  3. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Yuen, S.T., Davies, H., Chan, T.L., Ho, J.W., Bignell, G.R., Cox, C., Stephens, P., Edkins, S., Tsui, W.W., Chan, A.S., Futreal, P.A., Stratton, M.R., Wooster, R., Leung, S.Y. Cancer Res. (2002) [Pubmed]
  4. Lymphatic mapping establishes the role of BRAF gene mutation in papillary thyroid carcinoma. Kim, J., Giuliano, A.E., Turner, R.R., Gaffney, R.E., Umetani, N., Kitago, M., Elashoff, D., Hoon, D.S. Ann. Surg. (2006) [Pubmed]
  5. Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. Ball, D.W., Jin, N., Rosen, D.M., Dackiw, A., Sidransky, D., Xing, M., Nelkin, B.D. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  6. Functional characterization of the novel T599I-VKSRdel BRAF mutation in a follicular variant papillary thyroid carcinoma. De Falco, V., Giannini, R., Tamburrino, A., Ugolini, C., Lupi, C., Puxeddu, E., Santoro, M., Basolo, F. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  7. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. Pfister, S., Janzarik, W.G., Remke, M., Ernst, A., Werft, W., Becker, N., Toedt, G., Wittmann, A., Kratz, C., Olbrich, H., Ahmadi, R., Thieme, B., Joos, S., Radlwimmer, B., Kulozik, A., Pietsch, T., Herold-Mende, C., Gnekow, A., Reifenberger, G., Korshunov, A., Scheurlen, W., Omran, H., Lichter, P. J. Clin. Invest. (2008) [Pubmed]
  8. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cavé, H., Verloes, A., Okamoto, N., Hennekam, R.C., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., Ohashi, H., Wilson, L., Heron, D., Bonneau, D., Corona, G., Kaname, T., Naritomi, K., Baumann, C., Matsumoto, N., Kato, K., Kure, S., Matsubara, Y. Nat. Genet. (2006) [Pubmed]
  9. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Weisenberger, D.J., Siegmund, K.D., Campan, M., Young, J., Long, T.I., Faasse, M.A., Kang, G.H., Widschwendter, M., Weener, D., Buchanan, D., Koh, H., Simms, L., Barker, M., Leggett, B., Levine, J., Kim, M., French, A.J., Thibodeau, S.N., Jass, J., Haile, R., Laird, P.W. Nat. Genet. (2006) [Pubmed]
  10. High frequency of BRAF mutations in nevi. Pollock, P.M., Harper, U.L., Hansen, K.S., Yudt, L.M., Stark, M., Robbins, C.M., Moses, T.Y., Hostetter, G., Wagner, U., Kakareka, J., Salem, G., Pohida, T., Heenan, P., Duray, P., Kallioniemi, O., Hayward, N.K., Trent, J.M., Meltzer, P.S. Nat. Genet. (2003) [Pubmed]
  11. Endothelial apoptosis in Braf-deficient mice. Wojnowski, L., Zimmer, A.M., Beck, T.W., Hahn, H., Bernal, R., Rapp, U.R., Zimmer, A. Nat. Genet. (1997) [Pubmed]
  12. Mutations of the BRAF gene in human cancer. Davies, H., Bignell, G.R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M.J., Bottomley, W., Davis, N., Dicks, E., Ewing, R., Floyd, Y., Gray, K., Hall, S., Hawes, R., Hughes, J., Kosmidou, V., Menzies, A., Mould, C., Parker, A., Stevens, C., Watt, S., Hooper, S., Wilson, R., Jayatilake, H., Gusterson, B.A., Cooper, C., Shipley, J., Hargrave, D., Pritchard-Jones, K., Maitland, N., Chenevix-Trench, G., Riggins, G.J., Bigner, D.D., Palmieri, G., Cossu, A., Flanagan, A., Nicholson, A., Ho, J.W., Leung, S.Y., Yuen, S.T., Weber, B.L., Seigler, H.F., Darrow, T.L., Paterson, H., Marais, R., Marshall, C.J., Wooster, R., Stratton, M.R., Futreal, P.A. Nature (2002) [Pubmed]
  13. Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Weber, A., Hengge, U.R., Urbanik, D., Markwart, A., Mirmohammadsaegh, A., Reichel, M.B., Wittekind, C., Wiedemann, P., Tannapfel, A. Lab. Invest. (2003) [Pubmed]
  14. Establishment and characterization of cell lines from three human thyroid carcinomas: Responses to all-trans-retinoic acid and mutations in the BRAF gene. Koh, C.S., Ku, J.L., Park, S.Y., Kim, K.H., Choi, J.S., Kim, I.J., Park, J.H., Oh, S.K., Chung, J.K., Lee, J.H., Kim, W.H., Kim, C.W., Cho, B.Y., Park, J.G. Mol. Cell. Endocrinol. (2007) [Pubmed]
  15. Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Nikiforova, M.N., Ciampi, R., Salvatore, G., Santoro, M., Gandhi, M., Knauf, J.A., Thomas, G.A., Jeremiah, S., Bogdanova, T.I., Tronko, M.D., Fagin, J.A., Nikiforov, Y.E. Cancer Lett. (2004) [Pubmed]
  16. BRAF mutation in papillary thyroid carcinoma. Cohen, Y., Xing, M., Mambo, E., Guo, Z., Wu, G., Trink, B., Beller, U., Westra, W.H., Ladenson, P.W., Sidransky, D. J. Natl. Cancer Inst. (2003) [Pubmed]
  17. Suppression of BRAF(V599E) in human melanoma abrogates transformation. Hingorani, S.R., Jacobetz, M.A., Robertson, G.P., Herlyn, M., Tuveson, D.A. Cancer Res. (2003) [Pubmed]
  18. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. Sumimoto, H., Imabayashi, F., Iwata, T., Kawakami, Y. J. Exp. Med. (2006) [Pubmed]
  19. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. Melillo, R.M., Castellone, M.D., Guarino, V., De Falco, V., Cirafici, A.M., Salvatore, G., Caiazzo, F., Basolo, F., Giannini, R., Kruhoffer, M., Orntoft, T., Fusco, A., Santoro, M. J. Clin. Invest. (2005) [Pubmed]
  20. SPRY2 is an inhibitor of the ras/extracellular signal-regulated kinase pathway in melanocytes and melanoma cells with wild-type BRAF but not with the V599E mutant. Tsavachidou, D., Coleman, M.L., Athanasiadis, G., Li, S., Licht, J.D., Olson, M.F., Weber, B.L. Cancer Res. (2004) [Pubmed]
  21. Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma. Sommerer, F., Vieth, M., Markwarth, A., Röhrich, K., Vomschloss, S., May, A., Ell, C., Stolte, M., Hengge, U.R., Wittekind, C., Tannapfel, A. Oncogene (2004) [Pubmed]
  22. BRAF mutation in endometrial carcinoma and hyperplasia: correlation with KRAS and p53 mutations and mismatch repair protein expression. Feng, Y.Z., Shiozawa, T., Miyamoto, T., Kashima, H., Kurai, M., Suzuki, A., Konishi, I. Clin. Cancer Res. (2005) [Pubmed]
  23. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Wilhelm, S.M., Carter, C., Tang, L., Wilkie, D., McNabola, A., Rong, H., Chen, C., Zhang, X., Vincent, P., McHugh, M., Cao, Y., Shujath, J., Gawlak, S., Eveleigh, D., Rowley, B., Liu, L., Adnane, L., Lynch, M., Auclair, D., Taylor, I., Gedrich, R., Voznesensky, A., Riedl, B., Post, L.E., Bollag, G., Trail, P.A. Cancer Res. (2004) [Pubmed]
  24. Tumor Necrosis Factor-{alpha} Blocks Apoptosis in Melanoma Cells when BRAF Signaling Is Inhibited. Gray-Schopfer, V.C., Karasarides, M., Hayward, R., Marais, R. Cancer Res. (2007) [Pubmed]
  25. BRAF mutations in papillary carcinomas of the thyroid. Fukushima, T., Suzuki, S., Mashiko, M., Ohtake, T., Endo, Y., Takebayashi, Y., Sekikawa, K., Hagiwara, K., Takenoshita, S. Oncogene (2003) [Pubmed]
  26. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Giordano, T.J., Kuick, R., Thomas, D.G., Misek, D.E., Vinco, M., Sanders, D., Zhu, Z., Ciampi, R., Roh, M., Shedden, K., Gauger, P., Doherty, G., Thompson, N.W., Hanash, S., Koenig, R.J., Nikiforov, Y.E. Oncogene (2005) [Pubmed]
  27. BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumors. Tannapfel, A., Vomschloss, S., Karhoff, D., Markwarth, A., Hengge, U.R., Wittekind, C., Arnold, R., Hörsch, D. Am. J. Clin. Pathol. (2005) [Pubmed]
  28. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. Durante, C., Puxeddu, E., Ferretti, E., Morisi, R., Moretti, S., Bruno, R., Barbi, F., Avenia, N., Scipioni, A., Verrienti, A., Tosi, E., Cavaliere, A., Gulino, A., Filetti, S., Russo, D. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  29. BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis. Mitsutake, N., Miyagishi, M., Mitsutake, S., Akeno, N., Mesa, C., Knauf, J.A., Zhang, L., Taira, K., Fagin, J.A. Endocrinology (2006) [Pubmed]
  30. Absence of BRAF and NRAS mutations in uveal melanoma. Cruz, F., Rubin, B.P., Wilson, D., Town, A., Schroeder, A., Haley, A., Bainbridge, T., Heinrich, M.C., Corless, C.L. Cancer Res. (2003) [Pubmed]
  31. Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis. Xing, M., Cohen, Y., Mambo, E., Tallini, G., Udelsman, R., Ladenson, P.W., Sidransky, D. Cancer Res. (2004) [Pubmed]
  32. Inhibition of growth and invasive ability of melanoma by inactivation of mutated BRAF with lentivirus-mediated RNA interference. Sumimoto, H., Miyagishi, M., Miyoshi, H., Yamagata, S., Shimizu, A., Taira, K., Kawakami, Y. Oncogene (2004) [Pubmed]
  33. Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Gray-Schopfer, V.C., Cheong, S.C., Chong, H., Chow, J., Moss, T., Abdel-Malek, Z.A., Marais, R., Wynford-Thomas, D., Bennett, D.C. Br. J. Cancer (2006) [Pubmed]
  34. Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Denoyelle, C., Abou-Rjaily, G., Bezrookove, V., Verhaegen, M., Johnson, T.M., Fullen, D.R., Pointer, J.N., Gruber, S.B., Su, L.D., Nikiforov, M.A., Kaufman, R.J., Bastian, B.C., Soengas, M.S. Nat. Cell Biol. (2006) [Pubmed]
  35. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Samowitz, W.S., Albertsen, H., Herrick, J., Levin, T.R., Sweeney, C., Murtaugh, M.A., Wolff, R.K., Slattery, M.L. Gastroenterology (2005) [Pubmed]
  36. Coexpression of NRASQ61R and BRAFV600E in human melanoma cells activates senescence and increases susceptibility to cell-mediated cytotoxicity. Petti, C., Molla, A., Vegetti, C., Ferrone, S., Anichini, A., Sensi, M. Cancer Res. (2006) [Pubmed]
  37. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Calhoun, E.S., Jones, J.B., Ashfaq, R., Adsay, V., Baker, S.J., Valentine, V., Hempen, P.M., Hilgers, W., Yeo, C.J., Hruban, R.H., Kern, S.E. Am. J. Pathol. (2003) [Pubmed]
  38. BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Domingo, E., Niessen, R.C., Oliveira, C., Alhopuro, P., Moutinho, C., Espín, E., Armengol, M., Sijmons, R.H., Kleibeuker, J.H., Seruca, R., Aaltonen, L.A., Imai, K., Yamamoto, H., Schwartz, S., Hofstra, R.M. Oncogene (2005) [Pubmed]
  39. Mutations of the BRAF gene in squamous cell carcinoma of the head and neck. Weber, A., Langhanki, L., Sommerer, F., Markwarth, A., Wittekind, C., Tannapfel, A. Oncogene (2003) [Pubmed]
  40. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Deng, G., Bell, I., Crawley, S., Gum, J., Terdiman, J.P., Allen, B.A., Truta, B., Sleisenger, M.H., Kim, Y.S. Clin. Cancer Res. (2004) [Pubmed]
  41. Missense mutations of the BRAF gene in human lung adenocarcinoma. Naoki, K., Chen, T.H., Richards, W.G., Sugarbaker, D.J., Meyerson, M. Cancer Res. (2002) [Pubmed]
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