Mutant MRAS:SHOC2:PPP1CC complexes dephosphorylate inactive RAFs

Stable Identifier
R-HSA-9660538
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
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PP1-mediated dephosphorylation of RAF 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 promoting RAF signaling, activating mutations in SHOC2, MRAS and PP1 are associated with increased RAF pathway activity in Noonan syndrome (Cordeddu et al, 2009; Gripp et al, 2016; Motta et al, 2016; Higgin et al, 2017; Motta et al, 2019a,b; Young et al, 2018).

Literature References
PubMed ID Title Journal Year
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
31059601 Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy

Motta, M, Giancotti, A, Mastromoro, G, Chandramouli, B, Pinna, V, Pantaleoni, F, Di Giosaffatte, N, Petrini, S, Mazza, T, D'Ambrosio, V, Versacci, P, Ventriglia, F, Chillemi, G, Pizzuti, A, Tartaglia, M, De Luca, A

Hum. Mutat. 2019
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
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
30348783 SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis

Young, LC, Hartig, N, Boned Del Río, I, Sari, S, Ringham-Terry, B, Wainwright, JR, Jones, GG, McCormick, F, Rodriguez-Viciana, P

Proc. Natl. Acad. Sci. U.S.A. 2018
31108500 Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy

Motta, M, Sagi-Dain, L, Krumbach, OHF, Hahn, A, Peleg, A, German, A, Lissewski, C, Coppola, S, Pantaleoni, F, Kocherscheid, L, Altmüller, F, Schanze, D, Logeswaran, T, Chahrokh-Zadeh, S, Munzig, A, Nakhaei-Rad, S, Cavé, H, Ahmadian, MR, Tartaglia, M, Zenker, M

Hum. Mol. Genet. 2019
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
27466182 SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling

Motta, M, Chillemi, G, Fodale, V, Cecchetti, S, Coppola, S, Stipo, S, Cordeddu, V, Macioce, P, Gelb, BD, Tartaglia, M

Hum. Mol. Genet. 2016
28666118 RAS Proteins and Their Regulators in Human Disease

Simanshu, DK, Nissley, DV, McCormick, F

Cell 2017
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
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
protein serine/threonine phosphatase activity of mutant MRAS:SHOC2:PP1 complexes [plasma membrane]
Physical Entity
Activity
Normal reaction
Disease
Name Identifier Synonyms
Noonan syndrome 3490 Turner's phenotype, karyotype normal (disorder)
esophageal carcinoma 1107 carcinoma OF ESOPHAGUS, carcinoma of oesophagus, cancer of esophagus, cancer of oesophagus, carcinoma of esophagus (disorder), carcinoma of esophagus (disorder)
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Reviewed
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