Reactome | "Activator" RAF:YWHAB dimer binds RAS:GTP

"Activator" RAF:YWHAB dimer binds RAS:GTP

Stable Identifier

R-HSA-5672950

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

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Activation of RAS downstream of extracellular signals allows RAS:GTP to recruit BRAF to the plasma membrane, disrupting the pre-existing inactivating interaction between BRAF and the 14-3-3 protein YWHAB (Marais et al, 1997; Yamamori et al, 1995; reviewed in Cseh et al, 2014). BRAF, unique of the three mammalian RAF proteins, is constitutively phosphorylated on the conserved serine residue (446 in BRAF) in the N-terminal acidic motif (NtA). Constitutive negative charge in this region is critical for BRAF to function as an activator of other RAF molecules, allowing signal amplification (Marais et al, 1997; Mason et al, 1999; Wan et al, 2004; Garnett et al, 2005; Hu et al, 2013; reviewed in Cseh et al, 2014). RAS:GTP-bound BRAF heterodimerizes with additional RAF monomers, allowing cis-autophosphorylation in the activation loop of the second RAF protein. Once activated by BRAF in this manner, the 'receiver' kinase monomer is competent to dimerize with and transactivate other monomers in turn (Weber et al, 2001; Garnett et al, 2005; Hu et al, 2013; reviewed in Cseh et al, 2014). Intruigingly, the scaffold protein KSR1 is activated by BRAF in a manner analogous to other RAF monomers and can similarly act as a RAF activator once it is itself activated (Brennan et al, 2011; Ory et al, 2003; reviewed in Raabe and Rapp, 2003; Cseh et al, 2014).

Although this pathway shows PP2A-mediated dephosphorylation of RAF and transient displacement of 14-3-3 proteins as preceding RAS and plasma membrane binding of RAF proteins, the order and dependency of these events is not clear. Both membrane binding and 14-3-3 displacement also appear to be facilitated by an interaction between RAF and the cell cycle protein Prohibitin (PHB; Rajalingam et al, 2005; reviewed in Rajalingam and Rudel, 2005; Chowdhury et al, 2014).

Literature References

PubMed ID	Title	Journal	Year
11325826	Active Ras induces heterodimerization of cRaf and BRaf Weber, CK, Slupsky, JR, Kalmes, HA, Rapp, UR	Cancer Res.	2001
16041367	Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration Rajalingam, K, Wunder, C, Brinkmann, V, Churin, Y, Hekman, M, Sievers, C, Rapp, UR, Rudel, T	Nat. Cell Biol.	2005
12932339	Ras signaling: PP2A puts Ksr and Raf in the right place Raabe, T, Rapp, UR	Curr. Biol.	2003
24347342	Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway Chowdhury, I, Thompson, WE, Thomas, K	J. Cell. Physiol.	2014
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
7744815	Purification of a Ras-dependent mitogen-activated protein kinase kinase kinase from bovine brain cytosol and its identification as a complex of B-Raf and 14-3-3 proteins Yamamori, B, Kuroda, S, Shimizu, K, Fukui, K, Ohtsuka, T, Takai, Y	J. Biol. Chem.	1995
16294014	Ras-Raf signaling needs prohibitin Rajalingam, K, Rudel, T	Cell Cycle	2005
12932319	Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites Ory, S, Zhou, M, Conrads, TP, Veenstra, TD, Morrison, DK	Curr Biol	2003
23993095	Allosteric activation of functionally asymmetric RAF kinase dimers Hu, J, Stites, EC, Yu, H, Germino, EA, Meharena, HS, Stork, PJ, Kornev, AP, Taylor, SS, Shaw, AS	Cell	2013
10205168	Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation Mason, CS, Springer, CJ, Cooper, RG, Superti-Furga, G, Marshall, CJ, Marais, R	EMBO J.	1999
21441910	A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK Brennan, DF, Dar, AC, Hertz, NT, Chao, WC, Burlingame, AL, Shokat, KM, Barford, D	Nature	2011
24937142	"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway Cseh, B, Doma, E, Baccarini, M	FEBS Lett.	2014
9020159	Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases Marais, R, Light, Y, Paterson, HF, Mason, CS, Marshall, CJ	J. Biol. Chem.	1997
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