High kinase activity BRAF mutants bind MAP2Ks and MAPKs

Stable Identifier
R-HSA-6802912
Type
Reaction [binding]
Species
Homo sapiens
Compartment
cytosol
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
High kinase activity BRAF mutants bind MAP2Ks and MAPKs
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
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
25907612 Regulation of RAF protein kinases in ERK signalling

Lavoie, H, Therrien, M

Nat. Rev. Mol. Cell Biol. 2015
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
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
Input
Output
Participates
as an event of
This event is regulated
Negatively by
Regulator
p21 RAS:GTP:activated RAF1 homo/heterodimer:PEBP1 [plasma membrane] (Homo sapiens)
Normal reaction
MAP2Ks and MAPKs bind to the activated RAF complex (Homo sapiens)
Functional status

Gain of function of high kinase activity BRAF mutants [cytosol]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cardiofaciocutaneous syndrome DOID:0060233 CFC syndrome, cardio-facial-cutaneous syndrome
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cross References
Mondo
Authored
Rothfels, K  (2015-05-18)
Reviewed
Stephens, RM  (2016-08-05)
Created
Rothfels, K  (2015-10-02)
Cite Us!