High kinase activity BRAF mutants bind MAP2Ks and MAPKs

Stable Identifier
R-HSA-6802912
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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High-kinase activity BRAF mutants such as the prevalent V600E mutant bind MAP2K and MAPK proteins to activate signaling in a constitutive, RAS-independent manner (Wan et al, 2004; Garnett et al, 2005; Ritt et al, 2010; Roring et al, 2012; Freeman et al, 2013; reviewed in Lavoie and Therrien, 2015). These highly active BRAF mutations are thought to disrupt interactions between the DFG motif and the P loop that are required to hold RAF in the inactive, "DFG out" conformation. In this way, BRAF V600E and other highly active BRAF mutations render the protein constitutively active (Wan et al, 2004; reviewed in Lito et al, 2013; Lavoie and Therrien, 2015). Although highly active BRAF mutants can heterodimerize with and signal through RAF1, V600E BRAF is resistant to disruptions in the dimerization interface, has relaxed requirements for RAF1 activation loop phosphorylation, and is able to signal as a monomer (Garnett et al, 2005; Ritt et al, 2010; Roring et al, 2012; Freeman et al, 2013; reviewed in Lavoie and Therrien, 2015; Lito et al, 2013).

Literature References
PubMed ID Title Journal Year
22510884 Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling

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

EMBO J. 2012
25907612 Regulation of RAF protein kinases in ERK signalling

Lavoie, H, Therrien, M

Nat. Rev. Mol. Cell Biol. 2015
23352452 Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling

Freeman, AK, Ritt, DA, Morrison, DK

Mol. Cell 2013
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
24202393 Tumor adaptation and resistance to RAF inhibitors

Lito, P, Rosen, N, Solit, DB

Nat. Med. 2013
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
19933846 Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling

Ritt, DA, Monson, DM, Specht, SI, Morrison, DK

Mol. Cell. Biol. 2010
Participants
Participant Of
This event is regulated
Normal reaction
Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created