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

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

Stable Identifier

R-HSA-5672966

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

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

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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