RAF is paradoxically phosphorylated downstream of kinase-inactive RAF

Stable Identifier
Reaction [transition]
Homo sapiens
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The enhanced dimerization of inhibited or kinase dead versions of BRAF to RAF1/CRAF stimulates the phosphorylation and transactivation of RAF1 (Wan et al, 2004; Garnett et al, 2005; Heidorn et al, 2010; Poulikakos et al, 2010; Hatzivassiliou et al, 2010; reviewed in Samatar and Poulikakos, 2014; Lavoie and Therrien, 2015). Other evidence suggests that paradoxical activation of RAF1 by inhibited or inactive BRAF may result from relief of an inhibitory CRAF autophosphorylation event (Holderfield et al, 2013; reviewed in Holderfield, 2014).

Literature References
PubMed ID Title Journal Year
23680146 RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation

Holderfield, M, Merritt, H, Chan, J, Wallroth, M, Tandeske, L, Zhai, H, Tellew, J, Hardy, S, Hekmat-Nejad, M, Stuart, DD, McCormick, F, Nagel, TE

Cancer Cell 2013
25907612 Regulation of RAF protein kinases in ERK signalling

Lavoie, H, Therrien, M

Nat. Rev. Mol. Cell Biol. 2015
24957944 Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond

Holderfield, M, Deuker, MM, McCormick, F, McMahon, M

Nat. Rev. Cancer 2014
20130576 RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

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

Nature 2010
20141835 Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF

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

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

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

Mol. Cell 2005
25435214 Targeting RAS-ERK signalling in cancer: promises and challenges

Samatar, AA, Poulikakos, PI

Nat Rev Drug Discov 2014
15035987 Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF

Wan, PT, Garnett, MJ, Roe, SM, Lee, S, Niculescu-Duvaz, D, Good, VM, Jones, CM, Marshall, CJ, Springer, CJ, Barford, D, Marais, R

Cell 2004
20179705 RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

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

Nature 2010
Participant Of
Catalyst Activity
Catalyst Activity
protein serine/threonine/tyrosine kinase activity of RAF activating kinases [plasma membrane]
Physical Entity
Normal reaction
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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