RAS mutants bind inactive RAF

Stable Identifier
R-HSA-6802908
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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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
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
24651010 Dragging ras back in the ring

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

Cancer Cell 2014
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
24202393 Tumor adaptation and resistance to RAF inhibitors

Lito, P, Solit, DB, Rosen, N

Nat. Med. 2013
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
21993244 RAS oncogenes: weaving a tumorigenic web

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

Nat. Rev. Cancer 2011
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
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
22292133 Mechanism of RAF isoform switching induced by oncogenic RAS in melanoma

Dumaz, N

Small GTPases 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
22589270 A comprehensive survey of Ras mutations in cancer

Lewis, PD, Mattos, C, Prior, IA

Cancer Res. 2012
Participants
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This event is regulated
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Normal reaction
Functional status

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

Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created
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