RAF activation depends on the formation of a side-by-side asymmetric homo- or heterodimer (formed from either 2 RAF monomers or a RAF monomer and KSR1) (Weber et al, 2001; Garnett et al, 2005; Rushworth et al, 2006; Rajakulendran et al, 2009; Hu et al, 2013). Dimerization is mediated by cluster of basic residues in the kinase domain, and mutation of these critical residues abrogates RAF activation (Rajakulendran et al, 2009). Dimerization is required for the 'activator' monomer to induce an allosteric change in the 'receiver' monomer that, in conjunction with activation loop phosphorylation, activates the kinase activity of the receiver (Hu et al, 2013). BRAF, by virtue of its constitutive negative charge in the NtA region, is uniquely able to function as an activator RAF without further modification, while RAF1, ARAF and KSR1 can function as activators only after being phosphorylated in the NtA region downstream of RAF pathway activation (Hu et al, 2013; Leicht et al, 2013; reviewed in Cseh et al, 2014). Homo and heterodimerization of RAF monomers may be promoted by association with MAP3K11, which interacts with BRAF and RAF1 in vitro and in vivo and which is required for RAF activation (Chadee et al, 2004a, Chadee et al, 2004b; Chadee et al, 2006).
Kalmes, HA, Rapp, UR, Weber, CK, Slupsky, JR
Kyriakis, JM, Chadee, DN
O'Neill, E, Rushworth, LK, Hindley, AD, Kolch, W
Stites, EC, Taylor, SS, Yu, H, Hu, J, Germino, EA, Meharena, HS, Stork, PJ, Kornev, AP, Shaw, AS
Baccarini, M, Cseh, B, Doma, E
Sicheri, F, Sahmi, M, Rajakulendran, T, Lefrancois, M, Therrien, M
Kyriakis, JM, Gutmann, DH, Luo, Z, Hung, G, Xu, D, Andalibi, A, Lim, DJ, Chadee, DN
Garnett, MJ, Barford, D, Paterson, H, Rana, S, Marais, R
Zhu, J, Bronisz, A, Balan, V, Tzivion, G, Rana, A, Leicht, DT, Kaplun, A
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