Reactome | MRAS:SHOC2:PPP1CC dephosphorylates inactive RAFs

MRAS:SHOC2:PPP1CC dephosphorylates inactive RAFs

Stable Identifier

R-HSA-9658445

Type

Reaction [transition]

Species

Homo sapiens

Compartment

plasma membrane, cytosol

ReviewStatus

5/5

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MRAS:SHOC2:PPP1CC dephosphorylates inactive RAFs

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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, Hartig, N, Muñoz-Alegre, M, Oses-Prieto, JA, Durdu, S, Bender, S, Vijayakumar, V, Vietri Rudan, M, Gewinner, C, Henderson, S, Jathoul, AP, Ghatrora, R, Lythgoe, MF, Burlingame, AL, Rodriguez-Viciana, P	Mol. Cell	2013
16041367	Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration Rajalingam, K, Wunder, C, Brinkmann, V, Churin, Y, Hekman, M, Sievers, C, Rapp, UR, Rudel, T	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 Gripp, KW, Aldinger, KA, Bennett, JT, Baker, L, Tusi, J, Powell-Hamilton, N, Stabley, D, Sol-Church, K, Timms, AE, Dobyns, WB	Am. J. Med. Genet. A	2016
24347342	Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway Chowdhury, I, Thompson, WE, Thomas, K	J. Cell. Physiol.	2014
28289718	Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy Higgins, EM, Bos, JM, Mason-Suares, H, Tester, DJ, Ackerman, JP, MacRae, CA, Sol-Church, K, Gripp, KW, Urrutia, R, Ackerman, MJ	JCI Insight	2017
16294014	Ras-Raf signaling needs prohibitin Rajalingam, K, Rudel, T	Cell Cycle	2005
28666118	RAS Proteins and Their Regulators in Human Disease Simanshu, DK, Nissley, DV, McCormick, F	Cell	2017
19684605	Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair Cordeddu, V, Di Schiavi, E, Pennacchio, LA, Ma'ayan, A, Sarkozy, A, Fodale, V, Cecchetti, S, Cardinale, A, Martin, J, Schackwitz, W, Lipzen, A, Zampino, G, Mazzanti, L, Digilio, MC, Martinelli, S, Flex, E, Lepri, F, Bartholdi, D, Kutsche, K, Ferrero, GB, Anichini, C, Selicorni, A, Rossi, C, Tenconi, R, Zenker, M, Merlo, D, Dallapiccola, B, Iyengar, R, Bazzicalupo, P, Gelb, BD, Tartaglia, M	Nat. Genet.	2009
12932319	Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites Ory, S, Zhou, M, Conrads, TP, Veenstra, TD, Morrison, DK	Curr Biol	2003
14530258	Membrane localization, oligomerization, and phosphorylation are required for optimal raf activation Goetz, CA, O'Neil, JJ, Farrar, MA	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 Rodriguez-Viciana, P, Oses-Prieto, J, Burlingame, A, Fried, M, McCormick, F	Mol. Cell	2006
11756411	Dephosphorylation of Ser-259 regulates Raf-1 membrane association Kubicek, M, Pacher, M, Abraham, D, Podar, K, Eulitz, M, Baccarini, M	J Biol Chem	2002
21779496	Raf family kinases: old dogs have learned new tricks Matallanas, D, Birtwistle, M, Romano, D, Zebisch, A, Rauch, J, von Kriegsheim, A, Kolch, W	Genes Cancer	2011