RAF1 mutants show enhanced heterodimerization with BRAF

Stable Identifier
R-HSA-9656213
Type
Reaction [binding]
Species
Homo sapiens
Compartment
plasma membrane, cytosol
ReviewStatus
5/5
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RAF1 mutants show enhanced heterodimerization with BRAF
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Mutations in RAF1 are common in RASopathies such as Noonan Syndrome, Costello Syndrome, LEOPARD Syndrome and others, and also occur at low frequency in some cancers (reviewed in Rauen, 2013; Samatar and Poulikakos, 2014). Germline mutations of RAF1 cluster in three regions: conserved region 2 (CR2) surrounding phosphorylation site S259, the activation segment, or conserved region 3 (CR3). Mutations in CR2 abrogate binding with 14-3-3 proteins and relieve this inhibitory interaction, increasing the downstream signaling presumably through increased availability of RAF1 for heterodimerization with BRAF (Kobayashi et al, 2010; Pandit et al, 2007; Razzaque et al, 2007; Krauthammer et al, 2015). Increased heterodimerization with BRAF has also been demonstrated for RAF1 proteins with mutations in CR3 and the activation domain, including for RAF1 mutants with decreased or absent kinase activity (Pandit et al, 2007; Wu et al, 2012).
Literature References
PubMed ID Title Journal Year
26214590 Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

Narayan, D, Straub, R, McCusker, JP, Kluger, HM, Ariyan, S, Pornputtapong, N, Ma, S, Schlessinger, J, Sznol, M, Krauthammer, M, Serin, M, Mane, S, Bosenberg, M, Wu, C, Halaban, R, Lifton, RP, Evans, P, Bacchiocchi, A, Kong, Y, Cheng, E

Nat. Genet. 2015
20052757 Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation

David, A, Aoki, Y, Kure, S, Matsubara, Y, Lapunzina, P, Gillessen-Kaesbach, G, Ohata, T, Verloes, A, Cavé, H, Kurosawa, K, Ando, T, Nakagawa, N, Narumi, Y, Ohashi, H, Takada, F, Philip, N, Mizuno, S, Tsuchiya, S, Sakazume, S, Niihori, T, Wieczorek, D, Fujiwara, I, Okamoto, N, Kawame, H, Kobayashi, T, Meneses, AG, Guliyeva, A

Hum. Mutat. 2010
17603482 Germline gain-of-function mutations in RAF1 cause Noonan syndrome

Kamisago, M, Nakagawa, M, Hirota, H, Muneuchi, J, Matsushima, M, Mizuno, K, Momma, K, Higashinakagawa, T, Komoike, Y, Fujiwara, Y, Amo, R, Furutani, M, Razzaque, MA, Nishizawa, T, Yagi, H, Katayama, H, Tokuyama, M, Matsuoka, R

Nat. Genet. 2007
25435214 Targeting RAS-ERK signalling in cancer: promises and challenges

Poulikakos, PI, Samatar, AA

Nat Rev Drug Discov 2014
22826437 Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants

Kim, KH, Araki, T, Gu, S, Yin, J, Simpson, J, Neel, BG, Hong, JH, Wu, X, Backx, PH, Bayliss, P

Mol. Cell. Biol. 2012
17603483 Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy

Ackerman, MJ, Marino, B, Zampino, G, Pennacchio, LA, Bos, JM, Martinelli, S, Gelb, BD, Mazzanti, L, Lepri, F, Faul, C, Rossi, C, López Siguero, JP, Esposito, G, Carta, C, Selicorni, A, Tenconi, R, Oishi, K, Pogna, EA, Torrente, I, Pandit, B, Dallapiccola, B, Mundel, P, Ustaszewska, A, Schackwitz, W, Sarkozy, A, Digilio, MC, Landstrom, A, Ommen, SR, Tartaglia, M

Nat Genet 2007
23875798 The RASopathies

Rauen, KA

Annu Rev Genomics Hum Genet 2013
Participants
Input
Output
Participates
as an event of
Normal reaction
RAS:GTP:'activator' RAF homo/heterodimerizes with other RAF monomers (Homo sapiens)
Functional status

Gain of function of RAF1 mutants [cytosol]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
Costello syndrome DOID:0050469 Faciocutaneoskeletal Syndrome, FCS SYNDROME
LEOPARD syndrome DOID:14291 Generalized lentiginosis, Multiple lentigines syndrome, Moynahan syndrome, Cardiocutaneous syndrome, Capute-Rimoin-Konigsmark-Esterly-Richardson syndrome, Lentiginosis profusa syndrome, Gorlin syndrome II, Progressive cardiomyopathic lentiginosis
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Noonan syndrome DOID:3490 Turner's phenotype, karyotype normal (disorder)
hypertrophic cardiomyopathy DOID:11984 familial hypertrophic cardiomyopathy, hypertrophic obstructive cardiomyopathy
Authored
Rothfels, K  (2019-10-25)
Reviewed
Gavathiotis, E  (2020-05-04)
Created
Rothfels, K  (2019-07-27)
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