RAS mutants bind inactive RAF

Stable Identifier
R-HSA-6802908
Type
Reaction [binding]
Species
Homo sapiens
Compartment
plasma membrane
ReviewStatus
5/5
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RAS mutants bind inactive RAF
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Downstream of oncogenic RAS, a number of pathways are activated in a cancer- and tissue-specific manner. Common effectors include the PI3K/AKT pathway, the RAL GDS pathway and the canonical RAF/MEK/ERK pathway (reviewed in Prior et al, 2012; Pylayeva-Gupta et al, 2011; Stephen et al, 2014). Activation of the RAF/MEK/ERK pathway depends on the recruitment and activation of RAF downstream of oncogenic RAS, although the extent of pathway activation and the importance of the different RAF genes varies among cancer types. For instance, RAF1 (also known as CRAF) is necessary for onset of RAS-driven non-small cell lung cancer and melanoma, but is dispensable in RAS-driven pancreatic ductal adenocarcinoma (Dumaz et al, 2006; Heidorn et al, 2010; Blasco et al, 2011; Karreth et al, 2011; Eser et al, 2013). And although BRAF activity is not required in RAS-driven melanoma as assessed by siRNA knockdown, in the presence of BRAF inhibitors, BRAF paradoxically contributes to pathway activation through dimerization-dependent activation of RAF1 (Dumaz et al, 2006; Heidorn et al, 2010; Poulikakos et al, 2010; Hatzivassiliou et al, 2010; reviewed in Dumaz, 2011; Lito et al, 2013).
Literature References
PubMed ID Title Journal Year
21993244 RAS oncogenes: weaving a tumorigenic web

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

Nat. Rev. Cancer 2011
22043453 C-Raf is required for the initiation of lung cancer by K-Ras(G12D)

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

Cancer Discov 2011
22292133 Mechanism of RAF isoform switching induced by oncogenic RAS in melanoma

Dumaz, N

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

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

Cancer Res. 2006
21514245 c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma

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

Cancer Cell 2011
20130576 RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

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

Nature 2010
20141835 Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF

Heidorn, SJ, Milagre, C, Whittaker, S, Nourry, A, Niculescu-Duvas, I, Dhomen, N, Hussain, J, Reis-Filho, JS, Springer, CJ, Pritchard, C, Marais, R

Cell 2010
24202393 Tumor adaptation and resistance to RAF inhibitors

Lito, P, Rosen, N, Solit, DB

Nat. Med. 2013
22589270 A comprehensive survey of Ras mutations in cancer

Prior, IA, Lewis, PD, Mattos, C

Cancer Res. 2012
23453624 Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer

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

Cancer Cell 2013
24651010 Dragging ras back in the ring

Stephen, AG, Esposito, D, Bagni, RK, McCormick, F

Cancer Cell 2014
20179705 RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

Poulikakos, PI, Zhang, C, Bollag, G, Shokat, KM, Rosen, N

Nature 2010
Participants
Input
Output
Participates
as an event of
This event is regulated
Positively by
Regulator
PHB [cytosol] (Homo sapiens)
Normal reaction
"Activator" RAF:YWHAB dimer binds RAS:GTP (Homo sapiens)
Functional status

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

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
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)
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