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Gene Review

RAF1  -  Raf-1 proto-oncogene, serine/threonine kinase

Homo sapiens

Synonyms: CMD1NN, CRAF, NS5, Proto-oncogene c-RAF, RAF, ...
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Disease relevance of RAF1


Psychiatry related information on RAF1


High impact information on RAF1


Chemical compound and disease context of RAF1


Biological context of RAF1

  • In 21 SCLC specimens (cell lines and tumor tissue) with normal DNA, used for comparison, we observed loss of heterozygosity at RAF1 (3p25) in ten of ten informative pairs by using two RFLPs from the RAF1 locus [2].
  • The cytogenetic and RFLP data suggest that the RAF1 locus at 3p25 is involved in the chromosomal deletion of SCLC [2].
  • Phylogenetic conservation of the makorin-2 gene, encoding a multiple zinc-finger protein, antisense to the RAF1 proto-oncogene [17].
  • Von Hippel-Lindau (VHL) disease was initially reported to be linked to the RAF1 oncogene (3p25) [18].
  • These results ordered RAF1 and D3S732 for the first time, confirmed the localisation of D3S1250 between RAF1 and D3S601 and determined the position of D3S651 with respect to other chromosome 3p25-p26 loci [19].

Anatomical context of RAF1


Associations of RAF1 with chemical compounds

  • The probes used in the analysis were p627 (RAF1) and pHeA12 (thyroid hormone receptor B) (3p24.1-3p22) [18].
  • Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4 [24].
  • Raf-1 is a serine/threonine kinase which is essential in cell growth and differentiation [25].
  • In marked contrast, perturbations in the PKC/Raf/MAPK pathway played an integral role in LC/BRY-mediated cell death based on evidence that pretreatment of cells with bisindolylmaleimide I, a selective PKC inhibitor, or geldanamycin, a benzoquinone ansamycin, which destabilizes and depletes Raf-1, markedly suppressed apoptosis [26].
  • Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways [27].
  • To investigate the potential farnesyl binding site(s) we prepared several N-terminal fragments of C-RAF and found that in the presence of cysteine-rich domain only the farnesylated form of H-Ras binds with high association rates [28].

Physical interactions of RAF1


Enzymatic interactions of RAF1


Co-localisations of RAF1


Regulatory relationships of RAF1


Other interactions of RAF1

  • This kinase is in turn activated via Raf-1 and MAPKK kinase (MAPKKK) [43].
  • Consistent with these data, CD40 signals up-regulate c-jun but not c-fos mRNA and alter the transcription factor ATF2 but not the Raf-1 protein [44].
  • JAK2, a member of the Janus kinase superfamily was found to interact functionally with Raf-1, a central component of the ras/mitogen-activated protein kinase signal transduction pathway [3].
  • Taken together, these data suggest that JAK2 and p21ras cooperate to activate Raf-1 [3].
  • RIN1 interacts with the "effector domain" of RAS and employs some RAS determinants that are common to, and others that are distinct from, those required for the binding of RAF1, a known RAS effector [45].

Analytical, diagnostic and therapeutic context of RAF1


  1. High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. Simon, R., Richter, J., Wagner, U., Fijan, A., Bruderer, J., Schmid, U., Ackermann, D., Maurer, R., Alund, G., Knönagel, H., Rist, M., Wilber, K., Anabitarte, M., Hering, F., Hardmeier, T., Schönenberger, A., Flury, R., Jäger, P., Fehr, J.L., Schraml, P., Moch, H., Mihatsch, M.J., Gasser, T., Sauter, G. Cancer Res. (2001) [Pubmed]
  2. Involvement of the RAF1 locus, at band 3p25, in the 3p deletion of small-cell lung cancer. Graziano, S.L., Pfeifer, A.M., Testa, J.R., Mark, G.E., Johnson, B.E., Hallinan, E.J., Pettengill, O.S., Sorenson, G.D., Tatum, A.H., Brauch, H. Genes Chromosomes Cancer (1991) [Pubmed]
  3. The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. Xia, K., Mukhopadhyay, N.K., Inhorn, R.C., Barber, D.L., Rose, P.E., Lee, R.S., Narsimhan, R.P., D'Andrea, A.D., Griffin, J.D., Roberts, T.M. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  4. Activated protooncogenes in human lung tumors from smokers. Reynolds, S.H., Anna, C.K., Brown, K.C., Wiest, J.S., Beattie, E.J., Pero, R.W., Iglehart, J.D., Anderson, M.W. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  5. Lysophosphatidic Acid Stimulates Ovarian Cancer Cell Migration via a Ras-MEK Kinase 1 Pathway. Bian, D., Su, S., Mahanivong, C., Cheng, R.K., Han, Q., Pan, Z.K., Sun, P., Huang, S. Cancer Res. (2004) [Pubmed]
  6. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Razzaque, M.A., 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) [Pubmed]
  7. Distribution, levels and phosphorylation of Raf-1 in Alzheimer's disease. Mei, M., Su, B., Harrison, K., Chao, M., Siedlak, S.L., Previll, L.A., Jackson, L., Cai, D.X., Zhu, X. J. Neurochem. (2006) [Pubmed]
  8. High frequency of BRAF mutations in nevi. Pollock, P.M., Harper, U.L., Hansen, K.S., Yudt, L.M., Stark, M., Robbins, C.M., Moses, T.Y., Hostetter, G., Wagner, U., Kakareka, J., Salem, G., Pohida, T., Heenan, P., Duray, P., Kallioniemi, O., Hayward, N.K., Trent, J.M., Meltzer, P.S. Nat. Genet. (2003) [Pubmed]
  9. Kinase suppressor of Ras is ceramide-activated protein kinase. Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X.H., Basu, S., McGinley, M., Chan-Hui, P.Y., Lichenstein, H., Kolesnick, R. Cell (1997) [Pubmed]
  10. Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway. Hughes, P.E., Renshaw, M.W., Pfaff, M., Forsyth, J., Keivens, V.M., Schwartz, M.A., Ginsberg, M.H. Cell (1997) [Pubmed]
  11. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Wang, H.G., Rapp, U.R., Reed, J.C. Cell (1996) [Pubmed]
  12. Activation of the Raf-1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells. Nemoto, K., Vogt, A., Oguri, T., Lazo, J.S. Prostate (2004) [Pubmed]
  13. Systemic delivery of RafsiRNA using cationic cardiolipin liposomes silences Raf-1 expression and inhibits tumor growth in xenograft model of human prostate cancer. Pal, A., Ahmad, A., Khan, S., Sakabe, I., Zhang, C., Kasid, U.N., Ahmad, I. Int. J. Oncol. (2005) [Pubmed]
  14. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. Yu, X., Guo, Z.S., Marcu, M.G., Neckers, L., Nguyen, D.M., Chen, G.A., Schrump, D.S. J. Natl. Cancer Inst. (2002) [Pubmed]
  15. Raf-1 kinase targets GA-binding protein in transcriptional regulation of the human immunodeficiency virus type 1 promoter. Flory, E., Hoffmeyer, A., Smola, U., Rapp, U.R., Bruder, J.T. J. Virol. (1996) [Pubmed]
  16. Activation of Raf1 and the ERK pathway in response to l-ascorbic acid in acute myeloid leukemia cells. Park, S., Park, C.H., Hahm, E.R., Kim, K., Kimler, B.F., Lee, S.J., Park, H.K., Lee, S.H., Kim, W.S., Jung, C.W., Park, K., Riordan, H.D., Lee, J.H. Cell. Signal. (2005) [Pubmed]
  17. Phylogenetic conservation of the makorin-2 gene, encoding a multiple zinc-finger protein, antisense to the RAF1 proto-oncogene. Gray, T.A., Azama, K., Whitmore, K., Min, A., Abe, S., Nicholls, R.D. Genomics (2001) [Pubmed]
  18. Confirmation of linkage in von Hippel-Lindau disease. Vance, J.M., Small, K.W., Jones, M.A., Stajich, J.M., Yamaoka, L.H., Roses, A.D., Hung, W.Y., Pericak-Vance, M.A. Genomics (1990) [Pubmed]
  19. Physical mapping of chromosome 3p25-p26 by fluorescence in situ hybridisation (FISH). Phipps, M.E., Maher, E.R., Affara, N.A., Latif, F., Leversha, M.A., Ferguson-Smith, M.E., Nakamura, Y., Lerman, M., Zbar, B., Ferguson-Smith, M.A. Hum. Genet. (1993) [Pubmed]
  20. RAF1-activated MEK1 is found on the Golgi apparatus in late prophase and is required for Golgi complex fragmentation in mitosis. Colanzi, A., Sutterlin, C., Malhotra, V. J. Cell Biol. (2003) [Pubmed]
  21. Translocation (3;5)(p26;q13) in a patient with chronic T-cell lymphoproliferative disorder. Schmidt, H.H., Pirc-Danoewinata, H., Panzer-Grümayer, E.R., Sill, H., Sedlmayr, P., Neumeister, P., Linkesch, W., Haas, O.A. Cancer Genet. Cytogenet. (1998) [Pubmed]
  22. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Lin, A., Minden, A., Martinetto, H., Claret, F.X., Lange-Carter, C., Mercurio, F., Johnson, G.L., Karin, M. Science (1995) [Pubmed]
  23. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Garnett, M.J., Rana, S., Paterson, H., Barford, D., Marais, R. Mol. Cell (2005) [Pubmed]
  24. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Sasaki, A., Taketomi, T., Kato, R., Saeki, K., Nonami, A., Sasaki, M., Kuriyama, M., Saito, N., Shibuya, M., Yoshimura, A. Nat. Cell Biol. (2003) [Pubmed]
  25. Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro. Macdonald, S.G., Crews, C.M., Wu, L., Driller, J., Clark, R., Erikson, R.L., McCormick, F. Mol. Cell. Biol. (1993) [Pubmed]
  26. Synergistic induction of apoptosis in human leukemia cells (U937) exposed to bryostatin 1 and the proteasome inhibitor lactacystin involves dysregulation of the PKC/MAPK cascade. Vrana, J.A., Grant, S. Blood (2001) [Pubmed]
  27. Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways. Jia, W., Yu, C., Rahmani, M., Krystal, G., Sausville, E.A., Dent, P., Grant, S. Blood (2003) [Pubmed]
  28. B- and C-RAF display essential differences in their binding to Ras: the isotype-specific N terminus of B-RAF facilitates Ras binding. Fischer, A., Hekman, M., Kuhlmann, J., Rubio, I., Wiese, S., Rapp, U.R. J. Biol. Chem. (2007) [Pubmed]
  29. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Chen, J., Fujii, K., Zhang, L., Roberts, T., Fu, H. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  30. Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein. Chadee, D.N., Xu, D., Hung, G., Andalibi, A., Lim, D.J., Luo, Z., Gutmann, D.H., Kyriakis, J.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  31. The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells. Dang, A., Frost, J.A., Cobb, M.H. J. Biol. Chem. (1998) [Pubmed]
  32. A novel human phosphatidylethanolamine-binding protein resists tumor necrosis factor alpha-induced apoptosis by inhibiting mitogen-activated protein kinase pathway activation and phosphatidylethanolamine externalization. Wang, X., Li, N., Liu, B., Sun, H., Chen, T., Li, H., Qiu, J., Zhang, L., Wan, T., Cao, X. J. Biol. Chem. (2004) [Pubmed]
  33. Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase. Shimizu, M., Wang, W., Walch, E.T., Dunne, P.W., Epstein, H.F. FEBS Lett. (2000) [Pubmed]
  34. Identification of a C-terminal region that regulates mitogen-activated protein kinase kinase-1 cytoplasmic localization and ERK activation. Cha, H., Lee, E.K., Shapiro, P. J. Biol. Chem. (2001) [Pubmed]
  35. Apoptosis-linked gene-2 connects the Raf-1 and ASK1 signalings. Chen, C., Sytkowski, A.J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  36. Retinoic acid increases amount of phosphorylated RAF; ectopic expression of cFMS reveals that retinoic acid-induced differentiation is more strongly dependent on ERK2 signaling than induced GO arrest is. Yen, A., Varvayanis, S. In Vitro Cell. Dev. Biol. Anim. (2000) [Pubmed]
  37. The mammalian formin FHOD1 interacts with the ERK MAP kinase pathway. Boehm, M.B., Milius, T.J., Zhou, Y., Westendorf, J.J., Koka, S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  38. The Raf-1 kinase associates with vimentin kinases and regulates the structure of vimentin filaments. Janosch, P., Kieser, A., Eulitz, M., Lovric, J., Sauer, G., Reichert, M., Gounari, F., Büscher, D., Baccarini, M., Mischak, H., Kolch, W. FASEB J. (2000) [Pubmed]
  39. Protein kinase Czeta mediated Raf-1/extracellular-regulated kinase activation by daunorubicin. Mas, V.M., Hernandez, H., Plo, I., Bezombes, C., Maestre, N., Quillet-Mary, A., Filomenko, R., Demur, C., Jaffrézou, J.P., Laurent, G. Blood (2003) [Pubmed]
  40. Selective activation of MEK1 but not MEK2 by A-Raf from epidermal growth factor-stimulated Hela cells. Wu, X., Noh, S.J., Zhou, G., Dixon, J.E., Guan, K.L. J. Biol. Chem. (1996) [Pubmed]
  41. Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition. Tran, N.H., Frost, J.A. J. Biol. Chem. (2003) [Pubmed]
  42. 16K human prolactin inhibits vascular endothelial growth factor-induced activation of Ras in capillary endothelial cells. D'Angelo, G., Martini, J.F., Iiri, T., Fantl, W.J., Martial, J., Weiner, R.I. Mol. Endocrinol. (1999) [Pubmed]
  43. Constitutive mutant and putative regulatory serine phosphorylation site of mammalian MAP kinase kinase (MEK1). Pagès, G., Brunet, A., L'Allemain, G., Pouysségur, J. EMBO J. (1994) [Pubmed]
  44. Cross-linking CD40 on B cells preferentially induces stress-activated protein kinases rather than mitogen-activated protein kinases. Berberich, I., Shu, G., Siebelt, F., Woodgett, J.R., Kyriakis, J.M., Clark, E.A. EMBO J. (1996) [Pubmed]
  45. Protein binding and signaling properties of RIN1 suggest a unique effector function. Han, L., Wong, D., Dhaka, A., Afar, D., White, M., Xie, W., Herschman, H., Witte, O., Colicelli, J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  46. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Wilhelm, S.M., Carter, C., Tang, L., Wilkie, D., McNabola, A., Rong, H., Chen, C., Zhang, X., Vincent, P., McHugh, M., Cao, Y., Shujath, J., Gawlak, S., Eveleigh, D., Rowley, B., Liu, L., Adnane, L., Lynch, M., Auclair, D., Taylor, I., Gedrich, R., Voznesensky, A., Riedl, B., Post, L.E., Bollag, G., Trail, P.A. Cancer Res. (2004) [Pubmed]
  47. ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf. Dwivedi, Y., Rizavi, H.S., Conley, R.R., Pandey, G.N. Mol. Psychiatry (2006) [Pubmed]
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