BRAF (gene)
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene.[1][2] The B-Raf protein is involved in sending signals in cells and in cell growth.
The BRAF gene may be mutated and as a consequence, the normal functioning of the B-Raf protein may be altered.[3] Certain inherited BRAF mutations cause birth defects. Alternatively, other acquired mutations (oncogene) in adults may cause cancer. Drugs that treat those cancers by inhibiting B-Raf are being studied. On August 17, 2011, one of them, PLX4032 (Vemurafenib), was approved by FDA for treatment of late-stage melanoma as the first drug come out of fragment-based drug discovery.[4]
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[edit] Function
B-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion.[5]
[edit] Clinical significance
Mutations in the BRAF gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogene.
Inherited mutations in this gene cause cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance.[6]
Acquired mutations in this gene have also been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.[5]
The V600E mutation of the BRAF gene has been associated with Hairy Cell Leukemia in numerous studies.
[edit] B-raf inhibitors
Some pharmaceutical firms are developing specific inhibitors of mutated B-raf protein for anticancer use.[7] [8] One example is PLX4032 (RG7204), which was licensed by the US Food and Drug Administration as Zelboraf for the treatment of metastatic melanoma in August 2011.
More general B-raf inhibitors include GDC-0879, PLX-4720, Sorafenib Tosylate.
[edit] BRAF mutants
More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers from more than 80% in melanomas and nevi, to as little as 0-18% in other tumors, such as 1-3% in lung cancers and 5% in colorectal cancer.[9] In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers.[10] This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer, melanoma and non-small-cell lung cancer.[11][12][13][14][15][16][17] In June 2011, a team of Italian scientists used massively parallel sequencing to pinpoint mutation V600E as a likely driver mutation in 100% of cases of Hairy cell leukaemia.[18]
Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, A727V, etc and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions.[19] These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. In the same paper it has been reported that most of the mutants stimulate enhanced B-Raf kinase activity toward MEK. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK.
[edit] Interactions
BRAF (gene) has been shown to interact with YWHAB,[20][21] C-Raf,[22] AKT1[23] and HRAS.[24][25]
[edit] References
- ^ Sithanandam G, Kolch W, Duh FM, Rapp UR (December 1990). "Complete coding sequence of a human B-raf cDNA and detection of B-raf protein kinase with isozyme specific antibodies". Oncogene 5 (12): 1775–80. PMID 2284096.
- ^ Sithanandam G, Druck T, Cannizzaro LA, Leuzzi G, Huebner K, Rapp UR (April 1992). "B-raf and a B-raf pseudogene are located on 7q in man". Oncogene 7 (4): 795–9. PMID 1565476.
- ^ Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, 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 BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (June 2002). "Mutations of the BRAF gene in human cancer". Nature 417 (6892): 949–54. doi:10.1038/nature00766. PMID 12068308.
- ^ "FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer" (Press release). Genentech. http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=13567. Retrieved 2011-08-17.
- ^ a b "Entrez Gene: BRAF". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=673.
- ^ Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM, Young T, Neri G (November 2006). "The cardiofaciocutaneous syndrome". J. Med. Genet. 43 (11): 833–42. doi:10.1136/jmg.2006.042796. PMC 2563180. PMID 16825433. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2563180.
- ^ King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, Zhang SY, Kumar R, Rusnak DW, Takle AK, Wilson DM, Hugger E, Wang L, Karreth F, Lougheed JC, Lee J, Chau D, Stout TJ, May EW, Rominger CM, Schaber MD, Luo L, Lakdawala AS, Adams JL, Contractor RG, Smalley KS, Herlyn M, Morrissey MM, Tuveson DA, Huang PS (December 2006). "Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885". Cancer Res. 66 (23): 11100–5. doi:10.1158/0008-5472.CAN-06-2554. PMID 17145850.
- ^ Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G (February 2008). "Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity". Proc. Natl. Acad. Sci. U.S.A. 105 (8): 3041–6. doi:10.1073/pnas.0711741105. PMC 2268581. PMID 18287029. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2268581.
- ^ Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S (September 2003). "Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers". J. Clin. Endocrinol. Metab. 88 (9): 4393–7. doi:10.1210/jc.2003-030305. PMID 12970315. http://jcem.endojournals.org/cgi/content/abstract/88/9/4393.
- ^ Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, Iacopetta B, Soong R (April 2008). "Detection of BRAF V600E mutation by pyrosequencing". Pathology 40 (3): 295–8. doi:10.1080/00313020801911512. PMID 18428050.
- ^ Li WQ, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B (2006). "BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status". Mol. Cancer 5 (1): 2. doi:10.1186/1476-4598-5-2. PMC 1360090. PMID 16403224. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1360090.
- ^ Benlloch S, Payá A, Alenda C, Bessa X, Andreu M, Jover R, Castells A, Llor X, Aranda FI, Massutí B (November 2006). "Detection of BRAF V600E mutation in colorectal cancer: comparison of automatic sequencing and real-time chemistry methodology". J Mol Diagn 8 (5): 540–3. doi:10.2353/jmoldx.2006.060070. PMC 1876165. PMID 17065421. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1876165.
- ^ Deng G, Bell I, Crawley S, Gum J, Terdiman JP, Allen BA, Truta B, Sleisenger MH, Kim YS (January 2004). "BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer". Clin. Cancer Res. 10 (1 Pt 1): 191–5. doi:10.1158/1078-0432.CCR-1118-3. PMID 14734469.
- ^ Gear H, Williams H, Kemp EG, Roberts F (August 2004). "BRAF mutations in conjunctival melanoma". Invest. Ophthalmol. Vis. Sci. 45 (8): 2484–8. doi:10.1167/iovs.04-0093. PMID 15277467.
- ^ Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, Ono T, Albertson DG, Pinkel D, Bastian BC (December 2003). "Determinants of BRAF mutations in primary melanomas". J. Natl. Cancer Inst. 95 (24): 1878–90. doi:10.1093/jnci/djg123. PMID 14679157.
- ^ Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M, Marino C, Avenia N, Rossi ED, Fadda G, Cavaliere A, Ribacchi R, Falorni A, Pontecorvi A, Pacini F, Pinchera A, Santeusanio F (May 2004). "BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas". J. Clin. Endocrinol. Metab. 89 (5): 2414–20. doi:10.1210/jc.2003-031425. PMID 15126572.
- ^ Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, Romei C, Miccoli P, Pinchera A, Basolo F (October 2008). "BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study". J. Clin. Endocrinol. Metab. 93 (10): 3943–9. doi:10.1210/jc.2008-0607. PMID 18682506.
- ^ Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, Pucciarini A, Bigerna B, Pacini R, Wells VA, Sportoletti P, Pettirossi V, Mannucci R, Elliott O, Liso A, Ambrosetti A, Pulsoni A, Forconi F, Trentin L, Semenzato G, Inghirami G, Capponi M, Di Raimondo F, Patti C, Arcaini L, Musto P, Pileri S, Haferlach C, Schnittger S, Pizzolo G, Foà R, Farinelli L, Haferlach T, Pasqualucci L, Rabadan R, Falini B (June 2011). "BRAF mutations in hairy-cell leukemia". N. Engl. J. Med. 364 (24): 2305–15. doi:10.1056/NEJMoa1014209. PMID 21663470. Lay summary – Science Update blog: Cancer Research UK.
- ^ Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R (March 2004). "Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-Raf". Cell 116 (6): 855–67. doi:10.1016/S0092-8674(04)00215-6. PMID 15035987.
- ^ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1847948.
- ^ Qiu W, Zhuang S, von Lintig FC, Boss GR, Pilz RB (October 2000). "Cell type-specific regulation of B-Raf kinase by cAMP and 14-3-3 proteins". J. Biol. Chem. 275 (41): 31921–9. doi:10.1074/jbc.M003327200. PMID 10931830.
- ^ Weber CK, Slupsky JR, Kalmes HA, Rapp UR (May 2001). "Active Ras induces heterodimerization of cRaf and BRaf". Cancer Res. 61 (9): 3595–8. PMID 11325826.
- ^ Guan KL, Figueroa C, Brtva TR, Zhu T, Taylor J, Barber TD, Vojtek AB (September 2000). "Negative regulation of the serine/threonine kinase B-Raf by Akt". J. Biol. Chem. 275 (35): 27354–9. doi:10.1074/jbc.M004371200. PMID 10869359.
- ^ Stang S, Bottorff D, Stone JC (June 1997). "Interaction of activated Ras with Raf-1 alone may be sufficient for transformation of rat2 cells". Mol. Cell. Biol. 17 (6): 3047–55. PMC 232157. PMID 9154803. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=232157.
- ^ Reuter CW, Catling AD, Jelinek T, Weber MJ (March 1995). "Biochemical analysis of MEK activation in NIH3T3 fibroblasts. Identification of B-Raf and other activators". J. Biol. Chem. 270 (13): 7644–55. doi:10.1074/jbc.270.13.7644. PMID 7706312.
[edit] Further reading
- Sithanandam G, Kolch W, Duh FM, Rapp UR (1991). "Complete coding sequence of a human B-raf cDNA and detection of B-raf protein kinase with isozyme specific antibodies". Oncogene 5 (12): 1775–80. PMID 2284096. *Garnett MJ, Marais R (2004). "Guilty as charged: B-Raf is a human oncogene". Cancer Cell 6 (4): 313–9. doi:10.1016/j.ccr.2004.09.022. PMID 15488754.
- Quiros RM, Ding HG, Gattuso P, et al. (2005). "Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations". Cancer 103 (11): 2261–8. doi:10.1002/cncr.21073. PMID 15880523.
- Karbowniczek M, Henske EP (2006). "The role of tuberin in cellular differentiation: are B-Raf and MAPK involved?". Ann N Y Acad Sci 1059 (1): 168–73. doi:10.1196/annals.1339.045. PMID 16382052.
- Ciampi R, Nikiforov YE (2007). "RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis". Endocrinology 148 (3): 936–41. doi:10.1210/en.2006-0921. PMID 16946010. *Espinosa AV, Porchia L, Ringel MD (2007). "Targeting BRAF in thyroid cancer". British Journal of Cancer 96 (1): 16–20. doi:10.1038/sj.bjc.6603520. PMC 2360215. PMID 17179987. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2360215.
[edit] External links
- GeneReviews/NCBI/NIH/UW entry on Noonan syndrome
- GeneReviews/NCBI/NIH/UW entry on Cardiofaciocutaneous Syndrome
- GeneReviews/NCBI/NIH/UW entry on LEOPARD Syndrome
- "BRAF gene". NCI Dictionary of Cancer Terms. http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=561325. Retrieved 2007-11-25.
- Finding faults in BRAF - Cancer Research UK blog post about the discovery of cancer-causing BRAF mutations (incl video)
This article incorporates public domain material from the U.S. National Cancer Institute document "Dictionary of Cancer Terms". This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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