RAF is phosphorylated downstream of oncogenic RAS

Stable Identifier
Reaction [transition]
Homo sapiens
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In many cancer types, RAF1 (also known as CRAF) appears to be a critical initial effector of the ERK pathway downstream of activated RAS and also mediates pathway activation in the presence of WT BRAF plus BRAF inhibitors (Rushworth et al, 2006; Dumaz et al, 2006; Garnett et al, 2005; Karreth et al, 2011; Poulikakos et al, 2010; Heidorn et al, 2010; Roring et al, 2012; reviewed in Samatar et al, 2014; Lito et al, 2013). This activation depends largely on heterodimerization with BRAF, although homodimers also contribute (Weber et al, 2001; Rushworth et al, 2006). Activation of RAF downstream of mutant RAS appears to require full phosphorylation of the N-region and the activation loop, unlike the case in BRAF mutant cells, where RAF N-loop phosphorylation is dispensable (Garnett et al, 2005).
Literature References
PubMed ID Title Journal Year
11325826 Active Ras induces heterodimerization of cRaf and BRaf

Kalmes, HA, Rapp, UR, Weber, CK, Slupsky, JR

Cancer Res. 2001
22510884 Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling

Fiala, GJ, Herr, R, Röring, M, Heilmann, K, Schamel, WW, Saunders, DN, Halbach, S, Capper, D, Brummer, T, Braun, S, von Deimling, A, Eisenhardt, AE

EMBO J. 2012
22043453 C-Raf is required for the initiation of lung cancer by K-Ras(G12D)

Frese, KK, DeNicola, GM, Baccarini, M, Karreth, FA, Tuveson, DA

Cancer Discov 2011
17018604 In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling

Ogilvie, L, Dumaz, N, Martin, J, Bastian, BC, Hedley, D, Hayward, R, Springer, C, Marais, R, Curtin, JA

Cancer Res. 2006
16508002 Regulation and role of Raf-1/B-Raf heterodimerization

O'Neill, E, Rushworth, LK, Hindley, AD, Kolch, W

Mol. Cell. Biol. 2006
20141835 Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF

Reis-Filho, JS, Heidorn, SJ, Springer, CJ, Pritchard, C, Nourry, A, Milagre, C, Whittaker, S, Dhomen, N, Marais, R, Niculescu-Duvas, I, Hussain, J

Cell 2010
16364920 Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization

Garnett, MJ, Barford, D, Paterson, H, Rana, S, Marais, R

Mol. Cell 2005
24202393 Tumor adaptation and resistance to RAF inhibitors

Lito, P, Solit, DB, Rosen, N

Nat. Med. 2013
25435214 Targeting RAS-ERK signalling in cancer: promises and challenges

Poulikakos, PI, Samatar, AA

Nat Rev Drug Discov 2014
20179705 RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

Shokat, KM, Zhang, C, Bollag, G, Rosen, N, Poulikakos, PI

Nature 2010
Catalyst Activity

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

Normal reaction
Functional status

Gain of function of RAS mutants:GTP:RAF homo/heterodimer [plasma membrane]

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