BRAF and RAF fusion mutant dimers are phosphorylated

Stable Identifier
Reaction [transition]
Homo sapiens
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Fusion mutants of BRAF and RAF1 are believed to form constitutive dimers and activate downstream signaling independent of RAS and external stimuli (Jones et al, 2008; Cin et al, 2011; Palanisamy et al, 2010; Ciampi et al, 2005; Stransky et al, 2014; Hutchinson et al, 2013; Zhang et al, 2013; Lee et al, 2012; Ricarte-Filho et al, 2013; reviewed in Lavoie and Therrien et al, 2015). The RAF portion of the fusion mutants may undergo phosphorylation of the N-region and activation loops similar to WT as shown in this reaction, although this has not been studied in detail. While WT RAF phosphorylation happens in the context of a complex with with RAS, this is unlikely to be the case for the fusion mutants, as many of these proteins lack the N-terminal RAS binding domain (reviewed in Lavoie and Therrien, 2015).

Literature References
PubMed ID Title Journal Year
24345920 BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition

Hutchinson, KE, Lyle, PL, Puzanov, I, Sosman, JA, Pietenpol, JA, Lehmann, BD, Ross, JS, Lipson, D, Vnencak-Jones, CL, Stephens, PJ, Miller, VA, Otto, G, Pao, W

Clin. Cancer Res. 2013
15630448 Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer

Kerler, R, Fagin, JA, Rabes, HM, Nikiforov, YE, Knauf, JA, Gandhi, M, Ciampi, R, Zhu, Z, Nikiforova, MN

J. Clin. Invest. 2005
25907612 Regulation of RAF protein kinases in ERK signalling

Lavoie, H, Therrien, M

Nat. Rev. Mol. Cell Biol. 2015
21424530 Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma

Herr, R, Scheurlen, W, Jabado, N, Jacob, K, Gnekow, A, Collins, VP, Lichter, P, Pekrun, A, Falkenstein, F, Meyer, C, Remke, M, von Deimling, A, Witt, H, Korshunov, A, Pfister, SM, Marschalek, R, Cin, H, Bender, S, Benner, A, Omran, H, Olbrich, H, Van Anh, TN, Kulozik, AE, Witt, O, Lambert, S, Janzarik, WG, Brummer, T, Jones, DT

Acta Neuropathol. 2011
20526349 Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma

Shankar, S, Siddiqui, J, Kuefer, R, Chen, YB, Greenson, JK, Lafargue, CJ, Ramnarayanan, K, Han, B, Palanisamy, N, Demichelis, F, Esgueva, R, Dhanasekaran, SM, Giordano, TJ, Fullen, DR, Pflueger, D, Moeller, P, Rubin, MA, Maher, CA, Cao, Q, Cao, X, Ateeq, B, Banerjee, S, Bismar, TA, Tomlins, SA, Varambally, S, Kumar-Sinha, C, Chinnaiyan, AM, Johnson, TM, Suleman, K, Tan, P, Kalyana-Sundaram, S

Nat. Med. 2010
18974108 Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas

Collins, VP, Liu, L, Kocialkowski, S, Ichimura, K, Pearson, DM, B├Ącklund, LM, Jones, DT

Cancer Res. 2008
24135138 Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers

Fagin, JA, Thomas, GA, Viale, A, Ricarte-Filho, JC, Voza, F, Bogdanova, T, Knauf, JA, Montero-Conde, C, Li, S, Garcia-Rendueles, ME, Heguy, A, Mason, CE

J. Clin. Invest. 2013
25204415 The landscape of kinase fusions in cancer

Kim, JL, Schalm, S, Stransky, N, Lengauer, C, Cerami, E

Nat Commun 2014
22745804 A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation

Buckman, D, Pavlicek, A, Aparicio, S, Rejto, PA, Srinivasa, SP, Lee, NV, Ye, J, Ching, KA, Zhao, Y, Christensen, JG, Bagrodia, S, Lira, ME

PLoS ONE 2012
23583981 Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

Lu, C, Dooling, DJ, Qaddoumi, I, Parker, M, Ellison, DW, Rusch, M, Easton, J, Miller, CP, Hedlund, E, Vadodaria, B, Downing, JR, Orisme, W, Tatevossian, RG, Wilson, RK, Wang, J, Zhao, D, Sheer, D, Kriwacki, R, Lee, R, Huether, R, Becksfort, J, Shurtleff, S, Wu, G, Boop, FA, Kandoth, C, Chen, X, Ma, J, Boggs, K, Baker, SJ, Gajjar, A, Fulton, RS, Mardis, ER, Fulton, LL, Gilbertson, RJ, Cheng, J, Wei, L, Tang, B, Punchihewa, C, Dalton, JD, Song, G, Mulder, HL, Ochoa, K, Ding, L, Tang, C, Nagahawatte, P, Mullighan, CG, Zhang, J, Li, Y

Nat. Genet. 2013
Catalyst Activity

protein serine/threonine/tyrosine kinase activity of RAF activating kinases [plasma membrane]

Normal reaction
Functional status

Gain of function of BRAF/RAF fusion dimers [cytosol]

Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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