Phosphorylation of RAF1 mutants

Stable Identifier
R-HSA-9656212
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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RAF1 mutants in cancer and germline disorders such as Noonan syndrome undergo enhanced dimerization and activation with BRAF, leading to high levels of downstream signaling. This has been observed even in cases of RAF1 mutations with abrogated or impaired kinase activity (Razzaque et al, 2007; Pandit et al, 2007; Kobayashi et al, 2010; Wu et al, 2012; Krauthammer et al, 2015; reviewed in Rauen, 2013).

Literature References
PubMed ID Title Journal Year
26214590 Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

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

Nat. Genet. 2015
19467855 The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

Tidyman, WE, Rauen, KA

Curr. Opin. Genet. Dev. 2009
20052757 Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation

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

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

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

Nat. Genet. 2007
22826437 Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants

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

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

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

Nat Genet 2007
Participants
Participates
Catalyst Activity

protein serine/threonine/tyrosine kinase activity of RAF activating kinases [plasma membrane]

Normal reaction
Functional status

Gain of function of p21 RAS:GTP:RAF1 mutant heterodimers [plasma membrane]

Status
Disease
Name Identifier Synonyms
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
Costello syndrome DOID:0050469 Faciocutaneoskeletal Syndrome, FCS SYNDROME
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
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