RAF is paradoxically phosphorylated downstream of kinase-inactive RAF

Stable Identifier
R-HSA-6802941
Type
Reaction [transition]
Species
Homo sapiens
Compartment
plasma membrane
ReviewStatus
5/5
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RAF is paradoxically phosphorylated downstream of kinase-inactive RAF
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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
25907612 Regulation of RAF protein kinases in ERK signalling

Lavoie, H, Therrien, M

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

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

Nat. Rev. Cancer 2014
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
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
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
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
Participants
Input
Output
Participates
as an event of
Catalyst Activity

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

Physical Entity
RAF activating kinases [plasma membrane] (Homo sapiens)
Activity
protein serine/threonine/tyrosine kinase activity (GO:0004712)
Normal reaction
Phosphorylation of RAF (Homo sapiens)
Functional status

Gain of function of mutant RAS:inactive BRAF:RAF1 [plasma membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Rothfels, K  (2015-05-18)
Reviewed
Stephens, RM  (2016-08-05)
Created
Rothfels, K  (2015-10-02)
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