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Gene Review

Raf1  -  v-raf-leukemia viral oncogene 1

Rattus norvegicus

Synonyms: Proto-oncogene c-RAF, RAF proto-oncogene serine/threonine-protein kinase, Raf, Raf-1, cRaf
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Disease relevance of Raf1

  • Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation [1].
  • Activation of Raf-1 during experimental gastric ulcer healing is Ras-mediated and protein kinase C-independent [2].
  • We have used the baculovirus/Sf9 insect cell system to elucidate the regulatory relationships between pp60v-src, p21v-ras, MAP kinase (p44erk1/mapk), and Raf-1 [3].
  • Phosphorylation of Erk1/2 in response to stimulation of the alpha2A-AR is effectively attenuated by pretreatment with pertussis toxin or by coexpression of a Gbetagamma subunit complex sequestrant peptide (betaARK1ct) and dominant-negative mutants of Ras (N17-Ras), mSOS1 (SOS-Pro), and Raf (DeltaN-Raf) [4].
  • Affinity with Raf is sufficient for Ras to efficiently induce rat mammary carcinomas [5].

Psychiatry related information on Raf1


High impact information on Raf1

  • However, we also found that Ras is an effective promoter of apoptosis, through the Raf pathway [8].
  • In vivo, dominant negative Ras mutant N17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in PC12 cells, and transfection of Ras, but not Raf, into COS cells results in a large elevation in the level of these lipids [9].
  • MEK kinase (MEKK) is part of a family of serine-threonine protein kinases that phosphorylate and activate MEKs independently of Raf [10].
  • Thus the forming of complexes containing MAPKK activity and Raf-1 protein are dependent upon the activity of Ras [11].
  • Finally, RKIP depletion or Raf hyperactivation reduces kinetochore localization and kinase activity of Aurora B, a regulator of the spindle checkpoint [12].

Chemical compound and disease context of Raf1

  • We conclude that members of the Src family of tyrosine kinases may be important in mediating the transcriptional changes occurring during cardiac myocyte hypertrophy and that Ras and Raf may be downstream effectors [13].
  • In contrast, expression of N17rac1, but not a truncated form of Raf-1, attenuated the morphological hypertrophy associated with phenylephrine stimulation [14].
  • Finally, substantial reduction of the angiotensin II-stimulated activation of Fyn, Raf-1, ERK, and expression of c-Fos by pertussis toxin pretreatment argues that G proteins of the Gi family as well as the Gq family are involved in angiotensin II-mediated mitogenic pathways in WB cells [15].

Biological context of Raf1


Anatomical context of Raf1

  • Cotransfection of the myocytes with constitutively active versions of Ras and MEK1 or an estrogen-inducible version of Raf1 also stimulated transcription from the Glut1 promoter [21].
  • Inhibition of endocytosis by dominant interfering dynamin-K44A blocked H-Ras but not K-Ras-mediated PC12 cell differentiation and selectively inhibited H-Ras- but not K-Ras-mediated Raf-1 activation in BHK cells [18].
  • The data also suggest a mechanism for returning Raf-1 to the cytosol after plasma membrane recruitment [18].
  • We used two mutants, RasS35 and RasG37, which differ in their ability to bind Raf-1, to examine Ras-dependent signaling in thyroid epithelial cells [22].
  • Expression of wild-type Rab5 or Rab5-Q79L increased the specific activity of K-Ras-activated Raf-1 but did not result in any redistribution of K-Ras from the plasma membrane to endosomes [18].

Associations of Raf1 with chemical compounds

  • These findings suggested that an early step in the pathway, possibly a step immediately before the activation of Raf1, was suppressed by low concentrations of dexamethasone [23].
  • H-Ras- but not K-Ras-mediated Raf-1 activation was also selectively dependent on phosphoinositide 3-kinase activity [18].
  • Expression of either a constitutively active form of the serine/threonine kinase Raf-1 or the Ras effector domain mutant 12V/35S, which retains binding to Raf but is impaired in binding to other Ras effectors, was also sufficient to confer partial radioresistance [24].
  • Furthermore, constitutively active Ras or Raf-1 can mimic the action of phenylephrine in inducing expression from these promoters [25].
  • Both H(2)O(2) and ONOO(-) activated Raf-1 [26].

Physical interactions of Raf1

  • We may conclude that GM1 and GM2 stimulate ERK1/2 via a pertussis toxin-sensitive G(i)-coupled receptor through a Raf-1 kinase-independent pathway [27].
  • Age-dependent decline in mitogenic stimulation of hepatocytes. Reduced association between Shc and the epidermal growth factor receptor is coupled to decreased activation of Raf and extracellular signal-regulated kinases [28].
  • We have shown that, heat shock activates Raf-1 kinase and causes an increase in phosphotyrosine content of the 52 kDa Shc protein accompanied by an increment in the amount of coimmunoprecipitated Grb2 [29].

Enzymatic interactions of Raf1

  • Raf is a serine/threonine kinase capable of phosphorylating and activating MEK [30].
  • Finally, an association of Ras and Raf with phosphorylated Bcl-2 protein was demonstrated in immunoprecipitates from apoptotic cells [31].

Regulatory relationships of Raf1


Other interactions of Raf1

  • Conditioned medium from wounded but not intact IEC-6 monolayers resulted in increased activity of ERK1, ERK2, and Raf-1 kinase [17].
  • Coexpressing constitutively active forms of Ras, Raf, or MAPK/ERK kinase 1 (MEK1) increased promoter activity dramatically [36].
  • Our results demonstrate that gastric ulceration significantly increases Raf-1 kinase activity, Grb2 and Ras protein, and Shc-Grb2 and Grb2-Sos complex levels [2].
  • Collectively, these data indicate that ONOO(-) activates EGFR and Raf-1, but these signaling intermediates are not required for ONOO(-)-induced ERK activation [26].
  • To investigate alternatives to the Ras/Raf/MEK/Erk pathway in promoting hair cell survival, cochlear explants were exposed to gentamicin combined with several inhibitors of alternative pathways (LY294002, calphostin C, SH-6, U73122) [37].

Analytical, diagnostic and therapeutic context of Raf1


  1. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Galve-Roperh, I., Sánchez, C., Cortés, M.L., del Pulgar, T.G., Izquierdo, M., Guzmán, M. Nat. Med. (2000) [Pubmed]
  2. Activation of Raf-1 during experimental gastric ulcer healing is Ras-mediated and protein kinase C-independent. Pai, R., Jones, M.K., Tomikawa, M., Tarnawski, A.S. Am. J. Pathol. (1999) [Pubmed]
  3. Raf-1 and p21v-ras cooperate in the activation of mitogen-activated protein kinase. Williams, N.G., Paradis, H., Agarwal, S., Charest, D.L., Pelech, S.L., Roberts, T.M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  4. Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. Della Rocca, G.J., van Biesen, T., Daaka, Y., Luttrell, D.K., Luttrell, L.M., Lefkowitz, R.J. J. Biol. Chem. (1997) [Pubmed]
  5. Affinity with Raf is sufficient for Ras to efficiently induce rat mammary carcinomas. McFarlin, D.R., Lindstrom, M.J., Gould, M.N. Carcinogenesis (2003) [Pubmed]
  6. The activation of B-Raf and Raf-1 after electroconvulsive shock in the rat hippocampus. Kang, U.G., Jeon, S.H., Lee, J.E., Joo, Y.H., Yi, J.S., Park, J.B., Juhnn, Y.S., Kim, Y.S. Neuropharmacology (2000) [Pubmed]
  7. Expression of the Raf-1 protein in rat brain during development and its hormonal regulation in hypothalamus. Whorf, R.C., Tobet, S.A. J. Neurobiol. (1992) [Pubmed]
  8. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Kauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, C., Coffer, P., Downward, J., Evan, G. Nature (1997) [Pubmed]
  9. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Rodriguez-Viciana, P., Warne, P.H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M.J., Waterfield, M.D., Downward, J. Nature (1994) [Pubmed]
  10. Ras-dependent growth factor regulation of MEK kinase in PC12 cells. Lange-Carter, C.A., Johnson, G.L. Science (1994) [Pubmed]
  11. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Moodie, S.A., Willumsen, B.M., Weber, M.J., Wolfman, A. Science (1993) [Pubmed]
  12. Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Eves, E.M., Shapiro, P., Naik, K., Klein, U.R., Trakul, N., Rosner, M.R. Mol. Cell (2006) [Pubmed]
  13. Oncogenic src, raf, and ras stimulate a hypertrophic pattern of gene expression and increase cell size in neonatal rat ventricular myocytes. Fuller, S.J., Gillespie-Brown, J., Sugden, P.H. J. Biol. Chem. (1998) [Pubmed]
  14. A requirement for the rac1 GTPase in the signal transduction pathway leading to cardiac myocyte hypertrophy. Pracyk, J.B., Tanaka, K., Hegland, D.D., Kim, K.S., Sethi, R., Rovira, I.I., Blazina, D.R., Lee, L., Bruder, J.T., Kovesdi, I., Goldshmidt-Clermont, P.J., Irani, K., Finkel, T. J. Clin. Invest. (1998) [Pubmed]
  15. Angiotensin II induces diverse signal transduction pathways via both Gq and Gi proteins in liver epithelial cells. Tsygankova, O.M., Peng, M., Maloney, J.A., Hopkins, N., Williamson, J.R. J. Cell. Biochem. (1998) [Pubmed]
  16. Activation of the mitogen-activated protein kinase/cytosolic phospholipase A2 pathway in a rat mast cell line. Indications of different pathways for release of arachidonic acid and secretory granules. Hirasawa, N., Santini, F., Beaven, M.A. J. Immunol. (1995) [Pubmed]
  17. Rapid mitogen-activated protein kinase activation by transforming growth factor alpha in wounded rat intestinal epithelial cells. Göke, M., Kanai, M., Lynch-Devaney, K., Podolsky, D.K. Gastroenterology (1998) [Pubmed]
  18. H-Ras signaling and K-Ras signaling are differentially dependent on endocytosis. Roy, S., Wyse, B., Hancock, J.F. Mol. Cell. Biol. (2002) [Pubmed]
  19. Raf and fibroblast growth factor phosphorylate Elk1 and activate the serum response element of the immediate early gene pip92 by mitogen-activated protein kinase-independent as well as -dependent signaling pathways. Chung, K.C., Gomes, I., Wang, D., Lau, L.F., Rosner, M.R. Mol. Cell. Biol. (1998) [Pubmed]
  20. Reactive oxygen species modulate angiotensin II-induced beta-myosin heavy chain gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in neonatal rat cardiomyocytes. Shih, N.L., Cheng, T.H., Loh, S.H., Cheng, P.Y., Wang, D.L., Chen, Y.S., Liu, S.H., Liew, C.C., Chen, J.J. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  21. Transcriptional activation of the glucose transporter GLUT1 in ventricular cardiac myocytes by hypertrophic agonists. Montessuit, C., Thorburn, A. J. Biol. Chem. (1999) [Pubmed]
  22. Differential effects of protein kinase A on Ras effector pathways. Miller, M.J., Rioux, L., Prendergast, G.V., Cannon, S., White, M.A., Meinkoth, J.L. Mol. Cell. Biol. (1998) [Pubmed]
  23. Activation of the mitogen-activated protein kinase cascade is suppressed by low concentrations of dexamethasone in mast cells. Rider, L.G., Hirasawa, N., Santini, F., Beaven, M.A. J. Immunol. (1996) [Pubmed]
  24. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-independent signaling pathways. Grana, T.M., Rusyn, E.V., Zhou, H., Sartor, C.I., Cox, A.D. Cancer Res. (2002) [Pubmed]
  25. Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase. Thorburn, J., Carlson, M., Mansour, S.J., Chien, K.R., Ahn, N.G., Thorburn, A. Mol. Biol. Cell (1995) [Pubmed]
  26. Peroxynitrite targets the epidermal growth factor receptor, Raf-1, and MEK independently to activate MAPK. Zhang, P., Wang, Y.Z., Kagan, E., Bonner, J.C. J. Biol. Chem. (2000) [Pubmed]
  27. Gangliosides GM1 and GM2 induce vascular smooth muscle cell proliferation via extracellular signal-regulated kinase 1/2 pathway. Gouni-Berthold, I., Seul, C., Ko, Y., Hescheler, J., Sachinidis, A. Hypertension (2001) [Pubmed]
  28. Age-dependent decline in mitogenic stimulation of hepatocytes. Reduced association between Shc and the epidermal growth factor receptor is coupled to decreased activation of Raf and extracellular signal-regulated kinases. Palmer, H.J., Tuzon, C.T., Paulson, K.E. J. Biol. Chem. (1999) [Pubmed]
  29. The liver response to in vivo heat shock involves the activation of MAP kinases and RAF and the tyrosine phosphorylation of Shc proteins. Bendinelli, P., Piccoletti, R., Maroni, P., Bernelli-Zazzera, A. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  30. Involvement of Ras and Raf in the Gi-coupled acetylcholine muscarinic m2 receptor activation of mitogen-activated protein (MAP) kinase kinase and MAP kinase. Winitz, S., Russell, M., Qian, N.X., Gardner, A., Dwyer, L., Johnson, G.L. J. Biol. Chem. (1993) [Pubmed]
  31. Activated Ha-ras induces apoptosis by association with phosphorylated Bcl-2 in a mitogen-activated protein kinase-independent manner. Navarro, P., Valverde, A.M., Benito, M., Lorenzo, M. J. Biol. Chem. (1999) [Pubmed]
  32. Mutations in conserved regions 1, 2, and 3 of Raf-1 that activate transforming activity. Chan, E.Y., Stang, S.L., Bottorff, D.A., Stone, J.C. Mol. Carcinog. (2002) [Pubmed]
  33. Raf-independent deregulation of p38 and JNK mitogen-activated protein kinases are critical for Ras transformation. Pruitt, K., Pruitt, W.M., Bilter, G.K., Westwick, J.K., Der, C.J. J. Biol. Chem. (2002) [Pubmed]
  34. Activation of p38 MAPK induces cell cycle arrest via inhibition of Raf/ERK pathway during muscle differentiation. Lee, J., Hong, F., Kwon, S., Kim, S.S., Kim, D.O., Kang, H.S., Lee, S.J., Ha, J., Kim, S.S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  35. cGMP-elevating agents suppress proliferation of vascular smooth muscle cells by inhibiting the activation of epidermal growth factor signaling pathway. Yu, S.M., Hung, L.M., Lin, C.C. Circulation (1997) [Pubmed]
  36. Nerve growth factor uses Ras/ERK and phosphatidylinositol 3-kinase cascades to up-regulate the N-methyl-D-aspartate receptor 1 promoter. Liu, A., Prenger, M.S., Norton, D.D., Mei, L., Kusiak, J.W., Bai, G. J. Biol. Chem. (2001) [Pubmed]
  37. A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti. Chung, W.H., Pak, K., Lin, B., Webster, N., Ryan, A.F. J. Assoc. Res. Otolaryngol. (2006) [Pubmed]
  38. Baicalein inhibits Raf-1-mediated phosphorylation of MEK-1 in C6 rat glioma cells. Nakahata, N., Tsuchiya, C., Nakatani, K., Ohizumi, Y., Ohkubo, S. Eur. J. Pharmacol. (2003) [Pubmed]
  39. Cholecystokinin and EGF activate a MAPK cascade by different mechanisms in rat pancreatic acinar cells. Dabrowski, A., Groblewski, G.E., Schäfer, C., Guan, K.L., Williams, J.A. Am. J. Physiol. (1997) [Pubmed]
  40. Angiotensin II stimulates MAP kinase kinase kinase activity in vascular smooth muscle cells, Role of Raf. Liao, D.F., Duff, J.L., Daum, G., Pelech, S.L., Berk, B.C. Circ. Res. (1996) [Pubmed]
  41. Role of Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades in angiotensin II- and platelet-derived growth factor-induced vascular smooth muscle cell proliferation. Marrero, M.B., Schieffer, B., Li, B., Sun, J., Harp, J.B., Ling, B.N. J. Biol. Chem. (1997) [Pubmed]
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