"Activator" RAF:YWHAB dimer binds RAS:GTP

Stable Identifier
Homo sapiens
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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 (445 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

Kalmes, HA, Rapp, UR, Weber, CK, Slupsky, JR

Cancer Res. 2001
16041367 Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration

Brinkmann, V, Hekman, M, Wunder, C, Sievers, C, Rudel, T, Rajalingam, K, Churin, Y, Rapp, UR

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

Thomas, K, Chowdhury, I, Thompson, WE

J. Cell. Physiol. 2014
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
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

Kuroda, S, Takai, Y, Fukui, K, Shimizu, K, Yamamori, B, Ohtsuka, T

J. Biol. Chem. 1995
16294014 Ras-Raf signaling needs prohibitin

Rudel, T, Rajalingam, K

Cell Cycle 2005
12932319 Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites

Veenstra, TD, Ory, S, Zhou, M, Morrison, DK, Conrads, TP

Curr Biol 2003
23993095 Allosteric activation of functionally asymmetric RAF kinase dimers

Stites, EC, Taylor, SS, Yu, H, Hu, J, Germino, EA, Meharena, HS, Stork, PJ, Kornev, AP, Shaw, AS

Cell 2013
10205168 Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation

Springer, CJ, Superti-Furga, G, Cooper, RG, Mason, CS, Marshall, CJ, Marais, R

EMBO J. 1999
21441910 A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK

Shokat, KM, Brennan, DF, Hertz, NT, Chao, WC, Burlingame, AL, Barford, D, Dar, AC

Nature 2011
24937142 "RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway

Baccarini, M, Cseh, B, Doma, E

FEBS Lett. 2014
9020159 Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases

Paterson, HF, Light, Y, Mason, CS, Marshall, CJ, Marais, R

J. Biol. Chem. 1997
15035987 Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF

Niculescu-Duvaz, D, Lee, S, Marais, R, Marshall, CJ, Barford, D, Jones, CM, Good, VM, Springer, CJ, Wan, PT, Garnett, MJ, Roe, SM

Cell 2004
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