Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Jens RauchEmail author
  • Walter Kolch
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_610


Historical Background

A-RAF is a member of the RAF family of serine/threonine protein kinases comprising A-RAF B-RAF and RAF-1. In 1983 and 1986, the viral homologues of RAF were isolated during experiments with the aim to identify novel transforming genes. Viral RAF (v-RAF) homologus were encountered in two different viruses, the avian retrovirus Mill Hill 2 (MH2) and the murine sarcoma virus (MSV) 3611. While MH2 was isolated from a spontaneous chicken ovarian tumor, 3611-MSV was isolated from a mouse with lymphoma and lung adenocarcinoma. The name RAF derives from the observation that 3611-MSV increased the induction of fibrosarcoma in newborn NSF/N mice (rapidly accelerated fibrosarcoma, or RAF). These v-RAF genes originate from the mammalian proto-oncogene RAF-1 (or C-RAF) having incorporated the truncated CRAF kinase domain due to...

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  1. We apologize to all the colleagues, whose work, for reasons of space, could not be cited in this review.Google Scholar
  2. Baljuls A, Mueller T, Drexler H, Hekman M, Rapp U. Unique N-region determines low basal activity and limited inducibility of A-RAF kinase: the role of N-region in the evolutionary divergence of RAF kinase function in vertebrates. J Biol Chem. 2007;282:26575–90.  https://doi.org/10.1074/jbc.M702429200.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Baljuls A, Schmitz W, Mueller T, Zahedi R, Sickmann A, Hekman M, et al. Positive regulation of A-RAF by phosphorylation of isoform-specific hinge segment and identification of novel phosphorylation sites. J Biol Chem. 2008;283:27239–54.  https://doi.org/10.1074/jbc.M801782200.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Farrell J, Kelly C, Rauch J, Kida K, Garcia-Muñoz A, Monsefi N, et al. HGF induces epithelial-to-mesenchymal transition by modulating the mammalian hippo/MST2 and ISG15 pathways. J Proteome Res. 2014;13:2874–86.  https://doi.org/10.1021/pr5000285.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Huleihel M, Goldsborough M, Cleveland J, Gunnell M, Bonner T, Rapp U. Characterization of murine A-raf, a new oncogene related to the v-raf oncogene. Mol Cell Biol. 1986;6:2655–62.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Imielinski M, Greulich H, Kaplan B, Araujo L, Amann J, Horn L, et al. Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma. J Clin Invest. 2014;124:1582–6.  https://doi.org/10.1172/JCI72763.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Johnson L, James K, Chamberlain M, Anderson D. Identification of key residues in the A-Raf kinase important for phosphoinositide lipid binding specificity. Biochemistry. 2005;44:3432–40.  https://doi.org/10.1021/bi0487692.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Liu L, Channavajhala P, Rao V, Moutsatsos I, Wu L, Zhang Y, et al. Proteomic characterization of the dynamic KSR-2 interactome, a signaling scaffold complex in MAPK pathway. Biochim Biophys Acta. 2009;1794:1485–95.  https://doi.org/10.1016/j.bbapap.2009.06.016.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Liu X, Xiong C, Jia S, Zhang Y, Chen Y-G, Wang Q, et al. Araf kinase antagonizes Nodal-Smad2 activity in mesendoderm development by directly phosphorylating the Smad2 linker region. Nat Commun. 2013;4:1728.  https://doi.org/10.1038/ncomms2762.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, et al. Raf family kinases: old dogs have learned new tricks. Genes Cancer. 2011;2:232–60.  https://doi.org/10.1177/1947601911407323.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Mooz J, Oberoi-Khanuja TK, Harms GS, Wang W, Jaiswal BS, Seshagiri S, et al. Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration. Sci Signal. 2014;7:ra73.  https://doi.org/10.1126/scisignal.2005484.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Nelson DS, Quispel W, Badalian-Very G, van Halteren AGS, van den Bos C, Bovee JVMG, et al. Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood. 2014;123:3152–5.  https://doi.org/10.1182/blood-2013-06-511139.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Pritchard C, Bolin L, Slattery R, Murray R, McMahon M. Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene. Curr Biol. 1996;6:614–7.PubMedCrossRefGoogle Scholar
  14. Rauch J, Moran-Jones K, Albrecht V, Schwarzl T, Hunter K, Gires O, et al. c-Myc regulates RNA splicing of the A-Raf kinase and its activation of the ERK pathway. Cancer Res. 2011;71:4664–74.  https://doi.org/10.1158/0008-5472.CAN-10-4447.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Rauch J, O’Neill E, Mack B, Matthias C, Munz M, Kolch W, et al. Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription. Cancer Res. 2010;70:1679–88.  https://doi.org/10.1158/0008-5472.CAN-09-2740.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Rauch J, Vandamme D, Mack B, McCann B, Volinsky N, Blanco A, et al. Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation. Cell Death Differ. 2016;  https://doi.org/10.1038/cdd.2016.2.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Rebocho AP, Marais R. ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers. Oncogene. 2013;32:3207–12.  https://doi.org/10.1038/onc.2012.330.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Rushworth L, Hindley A, O’Neill E, Kolch W. Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol. 2006;26:2262–72.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Shilo A, Ben Hur V, Denichenko P, Stein I, Pikarsky E, Rauch J, et al. Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development. RNA. 2014;20:505–15.  https://doi.org/10.1261/rna.042259.113.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Sia D, Losic B, Moeini A, Cabellos L, Hao K, Revill K, et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun. 2015;6:6087.  https://doi.org/10.1038/ncomms7087.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Yokoyama T, Takano K, Yoshida A, Katada F, Sun P, Takenawa T, et al. DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation. J Cell Biol. 2007;177:781–93.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Systems Biology IrelandUniversity College DublinBelfield, DublinIreland
  2. 2.UCD Conway Institute of Biomolecular and Biomedical ResearchUniversity College DublinBelfield, DublinIreland