MRAS:SHOC2:PPP1CC dephosphorylates inactive RAFs

Stable Identifier
Reaction [transition]
Homo sapiens
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Activation of RAF upon growth factor stimulation depends on many factors including dephosphorylation, conformational change, dimerization, membrane recruitment and protein-protein interactions, among others (reviewed in Lavoie and Therien, 2015). In the inactive state, RAF1/CRAF is phosphorylated at S259 and S621 (corresponding to S365 and S729 in BRAF, and S214 and S582 in ARAF). These sites mediate the interaction with YWHAB/14-3-3 proteins (reviewed in Matallanas et al, 2011; Lavoie and Therien, 2015). Dephosphorylation of the S259 site by PP2A and or PP1 (also known as PPP1CC) disrupts interaction with 14-3-3 proteins and promotes a conformational change that exposes the membrane and RAS interacting RBD and CRD, facilitating recruitment of RAF to the plasma membrane (Kubicek et al, 2002; Goetz et al, 2003; Ory et al, 2003). PP1-mediated dephosphorylation occurs in the context of a ternary complex consisting of SHOC2 and the RAS protein family member MRAS in its GTP bound form (Rodriguez-Viciano et al, 2006; Young et al, 2013; reviewed in Simanshu et al, 2017). Consistent with a role of this ternary complex in activating RAF signaling, mutations in SHOC2, MRAS and PP1 are associated with increased RAF pathway activity in Noonan syndrome (Cordeddu et al, 2009; Gripp et al, 2016; Higgin et al, 2017; Young et al 2018).
Although S259 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
24211266 An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth

Young, LC, Ghatrora, R, Gewinner, C, Bender, S, Hartig, N, Burlingame, AL, Oses-Prieto, JA, Henderson, S, Vijayakumar, V, Jathoul, AP, Vietri Rudan, M, Rodriguez-Viciana, P, Lythgoe, MF, Muñoz-Alegre, M, Durdu, S

Mol. Cell 2013
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
25907612 Regulation of RAF protein kinases in ERK signalling

Lavoie, H, Therrien, M

Nat. Rev. Mol. Cell Biol. 2015
27264673 A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair

Aldinger, KA, Bennett, JT, Sol-Church, K, Baker, L, Timms, AE, Powell-Hamilton, N, Dobyns, WB, Gripp, KW, Tusi, J, Stabley, D

Am. J. Med. Genet. A 2016
24347342 Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway

Thomas, K, Chowdhury, I, Thompson, WE

J. Cell. Physiol. 2014
28289718 Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy

Tester, DJ, Sol-Church, K, Higgins, EM, MacRae, CA, Mason-Suares, H, Ackerman, JP, Bos, JM, Urrutia, R, Gripp, KW, Ackerman, MJ

JCI Insight 2017
16294014 Ras-Raf signaling needs prohibitin

Rudel, T, Rajalingam, K

Cell Cycle 2005
28666118 RAS Proteins and Their Regulators in Human Disease

McCormick, F, Nissley, DV, Simanshu, DK

Cell 2017
19684605 Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair

Zenker, M, Martinelli, S, Di Schiavi, E, Cordeddu, V, Ferrero, GB, Cardinale, A, Bartholdi, D, Merlo, D, Anichini, C, Iyengar, R, Tartaglia, M, Tenconi, R, Schackwitz, W, Cecchetti, S, Digilio, MC, Gelb, BD, Zampino, G, Pennacchio, LA, Bazzicalupo, P, Sarkozy, A, Ma'ayan, A, Kutsche, K, Fodale, V, Lipzen, A, Dallapiccola, B, Flex, E, Lepri, F, Martin, J, Selicorni, A, Rossi, C, Mazzanti, L

Nat. Genet. 2009
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
16630891 A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity

McCormick, F, Fried, M, Burlingame, A, Oses-Prieto, J, Rodriguez-Viciana, P

Mol. Cell 2006
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
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
Catalyst Activity

protein serine/threonine phosphatase activity of S-GCC MRAS:GTP:SHOC2:PP1 [plasma membrane]

Orthologous Events
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