Homo- or heterodimerization of RAF downstream of mutant RAS

Stable Identifier
R-HSA-6803240
Type
Reaction [BlackBoxEvent]
Species
Homo sapiens
Compartment
plasma membrane
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
Homo- or heterodimerization of RAF downstream of mutant RAS
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

Similar to the WT pathway, activation of RAF downstream of oncogenic RAS depends on homo- or heterodimerization of RAF, although the importance of RAF proteins varies among cancer types (Dumaz et al, 2006; Heidorn et al, 2010; Blasco et al, 2011; Karreth et al, 2011; Eser et al, 2013; Heidorn et al, 2010; Poulikakos et al, 2010; Hatzivassiliou et al, 2010; reviewed in Lito et al, 2013). A notable exception to this requirement for RAF dimerization is BRAF V600E, which is RAS-independent and constitutively active as a monomer (Roring et al, 2012; Brummer et al, 2006; Freeman et al, 2013; Garnett et al, 2005).

Literature References
PubMed ID Title Journal Year
16702958 Functional analysis of the regulatory requirements of B-Raf and the B-Raf(V600E) oncoprotein

Daly, RJ, Brummer, T, Reth, M, Misawa, Y, Martin, P, Herzog, S

Oncogene 2006
21993244 RAS oncogenes: weaving a tumorigenic web

Grabocka, E, Pylayeva-Gupta, Y, Bar-Sagi, D

Nat. Rev. Cancer 2011
21514245 c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma

Barbacid, M, Baccarini, M, Santamaría, D, Francoz, S, Cañamero, M, Charron, J, Dubus, P, Blasco, RB

Cancer Cell 2011
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
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
22589270 A comprehensive survey of Ras mutations in cancer

Lewis, PD, Mattos, C, Prior, IA

Cancer Res. 2012
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
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
22043453 C-Raf is required for the initiation of lung cancer by K-Ras(G12D)

Frese, KK, DeNicola, GM, Baccarini, M, Karreth, FA, Tuveson, DA

Cancer Discov 2011
17018604 In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling

Ogilvie, L, Dumaz, N, Martin, J, Bastian, BC, Hedley, D, Hayward, R, Springer, C, Marais, R, Curtin, JA

Cancer Res. 2006
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
24202393 Tumor adaptation and resistance to RAF inhibitors

Lito, P, Solit, DB, Rosen, N

Nat. Med. 2013
23453624 Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer

Michalski, CW, Schneider, G, Saur, D, Klein, S, Baccarini, M, Esposito, I, Rad, R, Dobler, M, Kong, B, Seidler, B, Rad, L, Schnieke, AE, Gottschalk, K, Alessi, DR, Arbeiter, A, Kind, AJ, Messer, M, Schlitter, AM, Eser, S, Schmid, RM, Hieber, M, Reiff, N

Cancer Cell 2013
Participants
Input
Output
Participates
as an event of
This event is regulated
Negatively by
Regulator
BRAP:KSR1:MARK3 [cytosol] (Homo sapiens)
Positively by
Regulator
MAP3K11 [cytosol] (Homo sapiens)
Normal reaction
RAS:GTP:'activator' RAF homo/heterodimerizes with other RAF monomers (Homo sapiens)
Functional status

Gain of function of RAS mutants:GTP:RAF [plasma membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Noonan syndrome DOID:3490 Turner's phenotype, karyotype normal (disorder)
Authored
Rothfels, K  (2015-05-18)
Reviewed
Stephens, RM  (2016-08-05)
Created
Rothfels, K  (2015-10-05)
Cite Us!