PP2A dephosphorylates inactive RAFs

Stable Identifier
Reaction [transition]
Homo sapiens
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Upon growth factor stimulation, RAF1 S259 (or S365 and S214 in BRAF and ARAF respectively) is dephosphorylated by PP2A and/or PP1, abrogating one of the YWHAB/14-3-3 binding sites (Terai et al, 2005; Ory et al, 2003; Kubicek et al, 2002; Jaumot et al, 2001; Rommel et al, 1996; reviewed in Roskoski, 2010; Matallanas et al, 2011). Release of 14-3-3 binding from the N-terminal site promotes a conformational change that exposes the membrane and RAS interacting RBD and CRD and facilitates recruitment of RAF to the plasma membrane where it binds RAS:GTP (Kubicek et al, 2002; Goetz et al, 2003; Ory et al, 2003). Dephosphorylation of S259/S365/S214 may also promote dimerization of RAF monomers by replacing the intramolecular 14-3-3 binding interaction with an intermolecular one (Rushworth et al, 2006; Weber et al, 2001; Ritt et al, 2010; reviewed in Matallanas et al, 2011). Although the PP2A-mediated dephosphorylation is shown as occurring before both YWHAB displacement and recruitment of RAF to the plasma membrane, the order of and relationship between these events is not completely clear. In addition, the displacement of 14-3-3 and recruitment of RAF1 to the membrane is also promoted by a direct interaction with 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
15711535 Ras binding opens c-Raf to expose the docking site for mitogen-activated protein kinase kinase

Matsuda, M, Terai, K

EMBO Rep. 2005
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
16508002 Regulation and role of Raf-1/B-Raf heterodimerization

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

Mol. Cell. Biol. 2006
24347342 Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway

Thomas, K, Chowdhury, I, Thompson, WE

J. Cell. Physiol. 2014
8637718 Activated Ras displaces 14-3-3 protein from the amino terminus of c-Raf-1

Rommel, C, Moelling, K, Noeldeke, J, Heinicke, T, Jones, D, Radziwill, G, Aitken, A, Lovri?, J

Oncogene 1996
16294014 Ras-Raf signaling needs prohibitin

Rudel, T, Rajalingam, K

Cell Cycle 2005
20674547 RAF protein-serine/threonine kinases: structure and regulation

Roskoski, R Jr

Biochem. Biophys. Res. Commun. 2010
19933846 Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling

Specht, SI, Monson, DM, Morrison, DK, Ritt, DA

Mol. Cell. Biol. 2010
11494123 Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions

Jaumot, M, Hancock, JF

Oncogene 2001
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
14530258 Membrane localization, oligomerization, and phosphorylation are required for optimal raf activation

O'Neil, JJ, Farrar, MA, Goetz, CA

J. Biol. Chem. 2003
21779496 Raf family kinases: old dogs have learned new tricks

Romano, D, Matallanas, D, Rauch, J, Zebisch, A, Birtwistle, M, Kolch, W, von Kriegsheim, A

Genes Cancer 2011
11756411 Dephosphorylation of Ser-259 regulates Raf-1 membrane association

Kubicek, M, Baccarini, M, Abraham, D, Pacher, M, Eulitz, M, Podar, K

J Biol Chem 2002
Catalyst Activity

protein serine/threonine phosphatase activity of PP2A [cytosol]

Orthologous Events
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