Paradoxical activation of RAF signaling by kinase inactive BRAF

Stable Identifier
R-HSA-6802955
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
Paradoxical activation of RAF signaling by kinase inactive BRAF
Click the image above or here to open this pathway in the Pathway Browser

While BRAF-specific inhibitors inhibit MAPK/ERK activation in the presence of the BRAF V600E mutant, paradoxical activation of ERK signaling has been observed after treatment of cells with inhibitor in the presence of WT BRAF (Wan et al, 2004; Garnett et al, 2005; Heidorn et al, 2010; Hazivassiliou et al, 2010; Poulikakos et al, 2010). This paradoxical ERK activation is also seen in cells expressing kinase-dead or impaired versions of BRAF such as D594V, which occur with low frequency in some cancers (Wan et al, 2004; Heidorn et al, 2010). Unlike BRAF V600E, which occurs exclusively of activating RAS mutations, kinase-impaired versions of BRAF are coincident with RAS mutations in human cancers, and indeed, paradoxical activation of ERK signaling in the presence of inactive BRAF is enhanced in the presence of oncogenic RAS (Heidorn et al, 2010; reviewed in Holderfield et al, 2014). Although the details remain to be worked out, paradoxical ERK activation in the presence of inactive BRAF appears to rely on enhanced dimerization with and transactivation of CRAF (Heidorn et al, 2010; Hazivassiliou et al, 2010; Poulikakos et al, 2010; Roring et al, 2012; Rajakulendran et al, 2009; Holderfield et al, 2013; Freeman et al, 2013; reviewed in Roskoski, 2010; Samatar and Poulikakos, 2014; Lavoie and Therrien, 2015). RAF inhibitors can promote association of RAF-RAS interaction and enhanced RAF dimerization through disruption of intramolecular interactions between the kinase domain and its N-terminal regulatory region. Moreover, specific BRAF inhibitors can only occupy one protomer within the transcactivated BRAF dimer due to negative co-operativity leading to paradoxical ERK activation. (Karoulia et al, 2016; Jin et al, 2017, reviewed in Karoulia et al, 2017).

Literature References
PubMed ID Title Journal Year
25907612 Regulation of RAF protein kinases in ERK signalling

Lavoie, H, Therrien, M

Nat. Rev. Mol. Cell Biol. 2015
19727074 A dimerization-dependent mechanism drives RAF catalytic activation

Sicheri, F, Sahmi, M, Rajakulendran, T, Lefrancois, M, Therrien, M

Nature 2009
24957944 Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond

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

Nat. Rev. Cancer 2014
23352452 Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling

Freeman, AK, Ritt, DA, Morrison, DK

Mol. Cell 2013
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
25435214 Targeting RAS-ERK signalling in cancer: promises and challenges

Poulikakos, PI, Samatar, AA

Nat Rev Drug Discov 2014
20674547 RAF protein-serine/threonine kinases: structure and regulation

Roskoski, R Jr

Biochem. Biophys. Res. Commun. 2010
29084939 RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition

David, M, Hilt, C, Sahmi, M, Lavoie, H, Jin, T, Hammell, A, Therrien, M

Nat Commun 2017
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
28984291 New perspectives for targeting RAF kinase in human cancer

Gavathiotis, E, Karoulia, Z, Poulikakos, PI

Nat. Rev. Cancer 2017
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
27523909 An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Poulikakos, PI, Gavathiotis, E, Wu, Y, Fagin, JA, Bollard, J, Ahmed, TA, Karoulia, Z, Krepler, C, Zhang, C, Xin, Q, Wu, X, Lujambio, A, Herlyn, M, Bollag, G

Cancer Cell 2016
23680146 RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation

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

Cancer Cell 2013
20130576 RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

Hatzivassiliou, G, Belvin, M, Stokoe, D, Ludlam, MJ, Alvarado, R, Morales, T, Jaiswal, BS, Seshagiri, S, Aliagas, I, Sideris, S, Malek, S, Koeppen, H, Gloor, SL, Vigers, G, Brandhuber, BJ, Liu, B, Yen, I, Friedman, LS, Anderson, DJ, Hoeflich, KP, Song, K

Nature 2010
15035987 Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF

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

Cell 2004
Participants
Events
Participates
as an event of
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cross References
BioModels Database
Authored
Rothfels, K  (2015-08-10)
Reviewed
Stephens, RM  (2016-08-05)
Created
Rothfels, K  (2015-10-02)
Cite Us!