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Gene Review

Raf1  -  v-raf-leukemia viral oncogene 1

Mus musculus

Synonyms: 6430402F14Rik, AA990557, BB129353, Craf, Craf1, ...
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Disease relevance of Raf1

  • With the use of dominant negative mutants of Ha-Ras and Raf-1, we investigated some of the early signaling events leading to the activation of NF-kappa B by hypoxia [1].
  • Constitutive activation of the Raf-1 oncogene resulted in malignant transformation as cytokine-independent FDC-P1 cells infected with a retrovirus encoding an activated Raf-1 protein formed tumors upon injection of immunocompromised mice [2].
  • Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload [3].
  • Here we show that infection of macrophages with Salmonella causes the activation and degradation of Raf-1, an important intermediate in macrophage proliferation and activation [4].
  • Ablation of the Raf-1 protein causes fetal liver apoptosis, embryonic lethality, and selective hypersensitivity to Fas-induced cell death [5].

High impact information on Raf1

  • Braf -/- embryos, unlike Araf -/- or Craf1 -/- embryos (L.W. et al., unpublished), show an increased number of endothelial precursor cells, dramatically enlarged blood vessels and apoptotic death of differentiated endothelial cells [6].
  • In addition, a Ras-independent role for Raf as a suppressor of programmed cell death has been suggested by the recent finding that Craf1 interacts with members of the Bcl-2 family at mitochondrial membranes [6].
  • Using a panel of phosphorylated peptides based on Raf-1, we have defined the 14-3-3 binding motif and show that most of the known 14-3-3 binding proteins contain the motif [7].
  • The Raf-1 serine/threonine kinase is a key component of the MAP kinase cascade, regulating both proliferation and commitment to cell fate [8].
  • Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization [8].

Chemical compound and disease context of Raf1


Biological context of Raf1

  • Because activation of the MAPK pathway is documented to promote DP differentiation in the absence of allelic exclusion, we characterized the properties of Vbeta chromatin within DP thymocytes generated by a constitutively active Raf1 (Raf-CAAX) transgene [11].
  • Three mutants: S218D, S222D and S218D/S222D in which we substituted the Raf1/MAPKKK-dependent regulatory phosphorylation sites by aspartic acid residues, displayed increased basal activity when expressed in fibroblasts [12].
  • No mutations but four genetic polymorphisms between C57BL/6 and C3H/He were found, with two of them reported as point mutations previously (op. cit.). The polymorphisms were utilized for allelic loss study of Raf1 locus [13].
  • These two genes together with Raf1 appear to be members of a large syntenic gene cluster that maps to human chromosome bands 3p25-->p26, mouse chromosome bands 6 C3-->E, and rat chromosome bands 4q41-->q42 [14].
  • Similarly, the poor proliferation of Raf-1(-/-) fibroblasts and hematopoietic cells cultivated in vitro is due to an increase in the apoptotic index of these cultures rather than to a cell cycle defect [15].

Anatomical context of Raf1

  • Finally, pull-down assays using the Ras-binding domain of Raf1 demonstrated that OSM directly activates K-Ras in fetal hepatocytes [16].
  • To examine the role of Ras in the activation of membrane-bound Raf1, raf1CAAX, and raf1(257L)CAAX, membrane-targeted variants of Raf1 and raf1(257L), respectively, were expressed in fibroblasts with or without coexpression of ras12V, 37G [17].
  • The transforming activity of artificially membrane-targeted Raf1 suggests that Ras-mediated recruitment of Raf1 to the plasma membrane is an important step in Raf1 activation [17].
  • Whether Ras simply promotes Raf1 association with caveolae membranes or also modulates subsequent activation events is presently unclear [17].
  • We propose that Raf1 plays a pivotal role in LPS-induced activation of the dendritic cells [18].

Associations of Raf1 with chemical compounds


Physical interactions of Raf1

  • Geldanamycin effects were attributed to a selective depletion of cellular Raf-1 that interrupted BCR-coupled activation of MEK1/2 and ERK [22].
  • We conclude that 14-3-3 is a latent co-activator bound to unactivated Raf-1 in quiescent cells and mediates mitogen-triggered but Ras-independent regulatory effects aimed directly at the kinase domain [23].
  • In addition to Raf, we show that v-Src, v-H-Ras and v-Mos activate HIV-LTR expression through the NF-kappa B binding sites and v-H-Ras-induced HIV-LTR expression is mediated by Raf-1 [24].

Enzymatic interactions of Raf1


Co-localisations of Raf1

  • Phosphorylated ezrin-positive dots were colocalized with actin-positive dots on the surface of some Raf-1 transfectants treated with SB203580 [26].

Regulatory relationships of Raf1


Other interactions of Raf1

  • Raf-1 from cells derived from raf-1(FF/FF) mice has no detectable activity towards MEK in vitro, and yet raf-1(FF/FF) mice survive to adulthood, are fertile and have an apparently normal phenotype [32].
  • These data suggest that Tpl-2 activates the MAPK cascade, perhaps through its participation in the assembly of Ras/Raf-1-containing multimolecular complexes [28].
  • Since Ras and Raf-1 have been previously shown to work downstream from membrane-associated tyrosine kinases such as Src, we determined if the Src membrane-associated kinase was also activated by low oxygen conditions [1].
  • These data suggest that signaling through the Raf-1 pathway is necessary for the optimal expression of p21 in chondrocytes and may play an important role in the control of bone formation [33].
  • Raf-1, a direct regulator of MKK1 and MKK2, was activated under these conditions, and a synergistic activation of MKK was observed upon coexpression of Raf-1 and MKP-1 [34].

Analytical, diagnostic and therapeutic context of Raf1

  • We have used gene targeting to generate a 'knockout' of the raf-1 gene in mice as well as a rafFF mutant version of endogenous Raf-1 with Y340FY341F mutations [32].
  • Heretofore, the biomarkers to detect 17-AAG bioactivity (Hsp70, Raf-1, and cyclin-dependent kinase 4) had to be analyzed by Western blot of cellular samples, either from tumor biopsies or peripheral blood leukocytes, a method that is both laborious and invasive [35].
  • We have used differential display PCR to search for mRNAs induced by delta Raf-1:ER, an estradiol-dependent form of Raf-1 kinase [36].
  • The significance of these interactions under physiological conditions was demonstrated by co-immunoprecipitation of Raf-1 and 14-3-3 from extracts of quiescent, but not mitogen-stimulated, NIH 3T3 cells [23].
  • Although ligation of both receptors induces Ras and Raf-1 activation, the downstream consequences of these early activation events are not well defined, except for the activation of extracellular signal-regulated kinases (ERK) [37].


  1. Hypoxic activation of nuclear factor-kappa B is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2). Koong, A.C., Chen, E.Y., Mivechi, N.F., Denko, N.C., Stambrook, P., Giaccia, A.J. Cancer Res. (1994) [Pubmed]
  2. Differential abilities of the Raf family of protein kinases to abrogate cytokine dependency and prevent apoptosis in murine hematopoietic cells by a MEK1-dependent mechanism. Hoyle, P.E., Moye, P.W., Steelman, L.S., Blalock, W.L., Franklin, R.A., Pearce, M., Cherwinski, H., Bosch, E., McMahon, M., McCubrey, J.A. Leukemia (2000) [Pubmed]
  3. Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Harris, I.S., Zhang, S., Treskov, I., Kovacs, A., Weinheimer, C., Muslin, A.J. Circulation (2004) [Pubmed]
  4. Protective role of Raf-1 in Salmonella-induced macrophage apoptosis. Jesenberger, V., Procyk, K.J., Rüth, J., Schreiber, M., Theussl, H.C., Wagner, E.F., Baccarini, M. J. Exp. Med. (2001) [Pubmed]
  5. Raf-1 sets the threshold of Fas sensitivity by modulating Rok-alpha signaling. Piazzolla, D., Meissl, K., Kucerova, L., Rubiolo, C., Baccarini, M. J. Cell Biol. (2005) [Pubmed]
  6. Endothelial apoptosis in Braf-deficient mice. Wojnowski, L., Zimmer, A.M., Beck, T.W., Hahn, H., Bernal, R., Rapp, U.R., Zimmer, A. Nat. Genet. (1997) [Pubmed]
  7. Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Muslin, A.J., Tanner, J.W., Allen, P.M., Shaw, A.S. Cell (1996) [Pubmed]
  8. Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Farrar, M.A., Alberol-Ila, n.u.l.l., Perlmutter, R.M. Nature (1996) [Pubmed]
  9. Activation of (His)6-Raf-1 in vitro by partially purified plasma membranes from v-Ras-transformed and serum-stimulated fibroblasts. Dent, P., Sturgill, T.W. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  10. Inhibition of MEK induces fas expression and apoptosis in lymphomas overexpressing Ras. Kalas, W., Kisielow, P., Strzadala, L. Leuk. Lymphoma (2002) [Pubmed]
  11. A role for MAPK in feedback inhibition of Tcrb recombination. Jackson, A.M., Krangel, M.S. J. Immunol. (2006) [Pubmed]
  12. Constitutively active mutants of MAP kinase kinase (MEK1) induce growth factor-relaxation and oncogenicity when expressed in fibroblasts. Brunet, A., Pagès, G., Pouysségur, J. Oncogene (1994) [Pubmed]
  13. Genetic analysis of Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes in 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas in B6C3F1 mice. Zhuang, S., Söderkvist, P. Mutat. Res. (2000) [Pubmed]
  14. Colocalization of the rat homolog of the von Hippel Lindau (Vhl) gene and the plasma membrane Ca++ transporting ATPase isoform 2 (Atp2b2) gene to rat chromosome bands 4q41.3-->42.1. Aldaz, C.M., Yeung, R.S., Latif, F., Lerman, M.I., Xiao, G., Trono, D., Walker, C.L. Cytogenet. Cell Genet. (1995) [Pubmed]
  15. Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. Mikula, M., Schreiber, M., Husak, Z., Kucerova, L., Rüth, J., Wieser, R., Zatloukal, K., Beug, H., Wagner, E.F., Baccarini, M. EMBO J. (2001) [Pubmed]
  16. K-Ras mediates cytokine-induced formation of E-cadherin-based adherens junctions during liver development. Matsui, T., Kinoshita, T., Morikawa, Y., Tohya, K., Katsuki, M., Ito, Y., Kamiya, A., Miyajima, A. EMBO J. (2002) [Pubmed]
  17. Physical association with ras enhances activation of membrane-bound raf (RafCAAX). Mineo, C., Anderson, R.G., White, M.A. J. Biol. Chem. (1997) [Pubmed]
  18. Raf1 plays a pivotal role in lipopolysaccharide-induced activation of dendritic cells. Nakayama, K., Ota, Y., Okugawa, S., Ise, N., Kitazawa, T., Tsukada, K., Kawada, M., Yanagimoto, S., Kimura, S. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  19. Induction of c-myc transcription by the v-Abl tyrosine kinase requires Ras, Raf1, and cyclin-dependent kinases. Zou, X., Rudchenko, S., Wong, K., Calame, K. Genes Dev. (1997) [Pubmed]
  20. Decrease in K-ras p21 and increase in Raf1 and activated Erk 1 and 2 in murine lung tumors initiated by N-nitrosodimethylamine and promoted by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Ramakrishna, G., Perella, C., Birely, L., Diwan, B.A., Fornwald, L.W., Anderson, L.M. Toxicol. Appl. Pharmacol. (2002) [Pubmed]
  21. Mitogen-activated protein kinase activation is not necessary for, but antagonizes, 3T3-L1 adipocytic differentiation. Font de Mora, J., Porras, A., Ahn, N., Santos, E. Mol. Cell. Biol. (1997) [Pubmed]
  22. Requirement for a hsp90 chaperone-dependent MEK1/2-ERK pathway for B cell antigen receptor-induced cyclin D2 expression in mature B lymphocytes. Piatelli, M.J., Doughty, C., Chiles, T.C. J. Biol. Chem. (2002) [Pubmed]
  23. Regulation of Raf-1 kinase activity by the 14-3-3 family of proteins. Li, S., Janosch, P., Tanji, M., Rosenfeld, G.C., Waymire, J.C., Mischak, H., Kolch, W., Sedivy, J.M. EMBO J. (1995) [Pubmed]
  24. Oncogene activation of HIV-LTR-driven expression via the NF-kappa B binding sites. Bruder, J.T., Heidecker, G., Tan, T.H., Weske, J.C., Derse, D., Rapp, U.R. Nucleic Acids Res. (1993) [Pubmed]
  25. Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Dumaz, N., Marais, R. J. Biol. Chem. (2003) [Pubmed]
  26. Phosphorylation of ezrin enhances microvillus length via a p38 MAP-kinase pathway in an immortalized mouse hepatic cell line. Lan, M., Kojima, T., Murata, M., Osanai, M., Takano, K., Chiba, H., Sawada, N. Exp. Cell Res. (2006) [Pubmed]
  27. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. Yamaguchi, O., Watanabe, T., Nishida, K., Kashiwase, K., Higuchi, Y., Takeda, T., Hikoso, S., Hirotani, S., Asahi, M., Taniike, M., Nakai, A., Tsujimoto, I., Matsumura, Y., Miyazaki, J., Chien, K.R., Matsuzawa, A., Sadamitsu, C., Ichijo, H., Baccarini, M., Hori, M., Otsu, K. J. Clin. Invest. (2004) [Pubmed]
  28. Tpl-2 acts in concert with Ras and Raf-1 to activate mitogen-activated protein kinase. Patriotis, C., Makris, A., Chernoff, J., Tsichlis, P.N. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  29. Kinase suppressor of ras is necessary for tumor necrosis factor alpha activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in intestinal epithelial cells. Yan, F., Polk, D.B. Cancer Res. (2001) [Pubmed]
  30. ERK1/2 is required for myoblast proliferation but is dispensable for muscle gene expression and cell fusion. Jones, N.C., Fedorov, Y.V., Rosenthal, R.S., Olwin, B.B. J. Cell. Physiol. (2001) [Pubmed]
  31. Raf-1 regulates Rho signaling and cell migration. Ehrenreiter, K., Piazzolla, D., Velamoor, V., Sobczak, I., Small, J.V., Takeda, J., Leung, T., Baccarini, M. J. Cell Biol. (2005) [Pubmed]
  32. MEK kinase activity is not necessary for Raf-1 function. Hüser, M., Luckett, J., Chiloeches, A., Mercer, K., Iwobi, M., Giblett, S., Sun, X.M., Brown, J., Marais, R., Pritchard, C. EMBO J. (2001) [Pubmed]
  33. The Raf-1/MEK/ERK pathway regulates the expression of the p21(Cip1/Waf1) gene in chondrocytes. Beier, F., Taylor, A.C., LuValle, P. J. Biol. Chem. (1999) [Pubmed]
  34. Feedback regulation of Raf-1 and mitogen-activated protein kinase (MAP) kinase kinases 1 and 2 by MAP kinase phosphatase-1 (MKP-1). Shapiro, P.S., Ahn, N.G. J. Biol. Chem. (1998) [Pubmed]
  35. Identification of new biomarkers for clinical trials of Hsp90 inhibitors. Zhang, H., Chung, D., Yang, Y.C., Neely, L., Tsurumoto, S., Fan, J., Zhang, L., Biamonte, M., Brekken, J., Lundgren, K., Burrows, F. Mol. Cancer Ther. (2006) [Pubmed]
  36. Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. McCarthy, S.A., Samuels, M.L., Pritchard, C.A., Abraham, J.A., McMahon, M. Genes Dev. (1995) [Pubmed]
  37. Mitogen-activated protein kinase activation through Fc epsilon receptor I and stem cell factor receptor is differentially regulated by phosphatidylinositol 3-kinase and calcineurin in mouse bone marrow-derived mast cells. Ishizuka, T., Chayama, K., Takeda, K., Hamelmann, E., Terada, N., Keller, G.M., Johnson, G.L., Gelfand, E.W. J. Immunol. (1999) [Pubmed]
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