AffiliationThe Institute of Cancer Research, London, UK.
MetadataShow full item record
AbstractThe RAF proteins are cytosolic protein kinases that regulate cell responses to extracellular signals. There are three RAF proteins in cells, ARAF, BRAF and CRAF, and recent studies have shown that the formation of complexes by these different isoforms has an important role in their activation, particularly in response to RAF inhibitors. Here, we investigated the role of ARAF in cancer cell signaling and examined the role of ARAF in mediating paradoxical activation of the MAPK pathway in cells treated with RAF inhibitors. We show that two mutations that occur in ARAF in cancer inactivate the kinase. We also show that ARAF is not functionally redundant with CRAF and cannot substitute for CRAF downstream of RAS. We further show that ARAF binds to and is activated by BRAF and that ARAF also forms complexes with CRAF. Critically, ARAF seems to stabilize BRAF:CRAF complexes in cells treated with RAF inhibitors and thereby regulate cell signaling in a subtle manner to ensure signaling efficiency.
CitationARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers. 2013, 32 (26):3207-12 Oncogene
- RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.
- Authors: Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N
- Issue date: 2010 Mar 18
- RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.
- Authors: Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S
- Issue date: 2010 Mar 18
- Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.
- Authors: Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, Rutkoski TJ, Wise S, Chun L, Zhang Y, Van Horn RD, Yin T, Zhang X, Yadav V, Chen SH, Gong X, Ma X, Webster Y, Buchanan S, Mochalkin I, Huber L, Kays L, Donoho GP, Walgren J, McCann D, Patel P, Conti I, Plowman GD, Starling JJ, Flynn DL
- Issue date: 2015 Sep 14
- Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration.
- Authors: Mooz J, Oberoi-Khanuja TK, Harms GS, Wang W, Jaiswal BS, Seshagiri S, Tikkanen R, Rajalingam K
- Issue date: 2014 Aug 5
- 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.
- Authors: Mitsutake N, Miyagishi M, Mitsutake S, Akeno N, Mesa C Jr, Knauf JA, Zhang L, Taira K, Fagin JA
- Issue date: 2006 Feb