RAS:GTP:'activator' RAF homo/heterodimerizes with other RAF monomers

Stable Identifier
Homo sapiens
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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).

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
15258589 MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation

Kyriakis, JM, Chadee, DN

Nat. Cell Biol. 2004
16508002 Regulation and role of Raf-1/B-Raf heterodimerization

O'Neill, E, Rushworth, LK, Hindley, AD, Kolch, W

Mol. Cell. Biol. 2006
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
24937142 "RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway

Baccarini, M, Cseh, B, Doma, E

FEBS Lett. 2014
19727074 A dimerization-dependent mechanism drives RAF catalytic activation

Sicheri, F, Sahmi, M, Rajakulendran, T, Lefrancois, M, Therrien, M

Nature 2009
16537381 Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein

Kyriakis, JM, Gutmann, DH, Luo, Z, Hung, G, Xu, D, Andalibi, A, Lim, DJ, Chadee, DN

Proc. Natl. Acad. Sci. U.S.A. 2006
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
23360980 MEK-1 activates C-Raf through a Ras-independent mechanism

Zhu, J, Bronisz, A, Balan, V, Tzivion, G, Rana, A, Leicht, DT, Kaplun, A

Biochim. Biophys. Acta 2013
15467451 A novel role for mixed lineage kinase 3 (MLK3) in B-Raf activation and cell proliferation

Kyriakis, JM, Chadee, DN

Cell Cycle 2004
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