proto oncogene proteins c raf


Summary: A ubiquitously expressed raf kinase subclass that plays an important role in SIGNAL TRANSDUCTION. The c-raf Kinases are MAP kinase kinase kinases that have specificity for MAP KINASE KINASE 1 and MAP KINASE KINASE 2.

Top Publications

  1. Chatterji B, Borlak J. Serum proteomics of lung adenocarcinomas induced by targeted overexpression of c-raf in alveolar epithelium identifies candidate biomarkers. Proteomics. 2007;7:3980-91 pubmed
    ..Disease association of these proteins in human malignancies has been reported. Thus, an identification of regulated serum proteins in this lung cancer disease model provides excellent opportunities for the search of novel biomarkers. ..
  2. Jeon S, Yoon J, Park Y, Jeong W, Kim S, Jho E, et al. Axin inhibits extracellular signal-regulated kinase pathway by Ras degradation via beta-catenin. J Biol Chem. 2007;282:14482-92 pubmed
    ..This study provides evidences for the role of the Ras-ERK pathway in carcinogenesis caused by mutations of the Wnt/beta-catenin pathway components. ..
  3. von Kriegsheim A, Pitt A, Grindlay G, Kolch W, Dhillon A. Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5. Nat Cell Biol. 2006;8:1011-6 pubmed
    ..Furthermore, depletion of endogenous PP5 increased cellular phospho-Ser 338 levels. Our results suggest that PP5 is a physiological regulator of Raf-1 signalling pathways. ..
  4. Kowluru R, Kowluru A, Kanwar M. Small molecular weight G-protein, H-Ras, and retinal endothelial cell apoptosis in diabetes. Mol Cell Biochem. 2007;296:69-76 pubmed
  5. Smalley K, Nathanson K, Flaherty K. Genetic subgrouping of melanoma reveals new opportunities for targeted therapy. Cancer Res. 2009;69:3241-4 pubmed publisher
    ..In the current review, we discuss how knowledge about these new melanoma subgroups may lead to improved strategies for treating melanomas harboring BRAF V600E mutations. ..
  6. Terai K, Matsuda M. The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf. EMBO J. 2006;25:3556-64 pubmed
    ..Thus, we propose that the hitherto unidentified function of the B-Raf amino-terminal region is to mediate calcium-dependent activation of B-Raf and the following MEK activation, which may occur in the absence of Ras activation. ..
  7. Alejandro E, Johnson J. Inhibition of Raf-1 alters multiple downstream pathways to induce pancreatic beta-cell apoptosis. J Biol Chem. 2008;283:2407-17 pubmed
    ..These studies identify Raf-1 as a critical anti-apoptotic kinase in pancreatic beta-cells and contribute to our understanding of survival signaling in this cell type. ..
  8. Smalley K, Xiao M, Villanueva J, Nguyen T, Flaherty K, Letrero R, et al. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009;28:85-94 pubmed publisher
    ..In summary, we have identified a group of melanomas with low-activity BRAF mutations that are reliant upon CRAF-mediated survival activity. ..
  9. Rütters H, Zurbig P, Halter R, Borlak J. Towards a lung adenocarcinoma proteome map: studies with SP-C/c-raf transgenic mice. Proteomics. 2006;6:3127-37 pubmed
    ..This map provides valuable insight into expression of pulmonary proteins associated with lung adenocarcinomas, some of which may be of utility as diagnostic markers in clinical trials. ..

More Information


  1. Dai P, Xiong W, Mei L. Erbin inhibits RAF activation by disrupting the sur-8-Ras-Raf complex. J Biol Chem. 2006;281:927-33 pubmed
    ..These results demonstrate a regulatory role of Erbin in the Ras-Raf-MEK pathway, suggesting that Erbin may inhibit ERK activation by disrupting the Sur-8-Ras/Raf interaction. ..
  2. Plowman S, Ariotti N, Goodall A, Parton R, Hancock J. Electrostatic interactions positively regulate K-Ras nanocluster formation and function. Mol Cell Biol. 2008;28:4377-85 pubmed publisher
    ..Together, these data illustrate that Ras nanocluster composition regulates effector recruitment and highlight the importance of lipid/protein nanoscale environments to the activation of signaling cascades. ..
  3. 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 pubmed
  4. Fujioka A, Terai K, Itoh R, Aoki K, Nakamura T, Kuroda S, et al. Dynamics of the Ras/ERK MAPK cascade as monitored by fluorescent probes. J Biol Chem. 2006;281:8917-26 pubmed
    ..This prediction was confirmed experimentally by decreasing the level of Raf using the small interfering RNA technique. This observation verified the usefulness of the parameters collected in this study. ..
  5. Montagut C, Sharma S, Shioda T, McDermott U, Ulman M, Ulkus L, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853-61 pubmed publisher
    ..Geldanamycin effectively promotes the degradation of CRAF, thereby revealing a potential therapeutic strategy to overcome resistance to RAF inhibition in a subset of BRAF mutant tumors. ..
  6. Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D, Curtin J, et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006;66:9483-91 pubmed
    ..These data have important implications for the development of therapeutic strategies to treat this life-threatening disease. ..
  7. Beith J, Alejandro E, Johnson J. Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. Endocrinology. 2008;149:2251-60 pubmed publisher
    ..These findings have significant implications for the understanding of the regulation of beta-cell mass in both the hyperinsulinemic and insulin-deficient states that occur in the various forms of diabetes. ..
  8. Cekanova M, Majidy M, Masi T, Al Wadei H, Schuller H. Overexpressed Raf-1 and phosphorylated cyclic adenosine 3'-5'-monophosphatate response element-binding protein are early markers for lung adenocarcinoma. Cancer. 2007;109:1164-73 pubmed
    ..The current results indicated that RAF-1 and P-CREB may contribute to the development of a significant subset of human lung adenocarcinomas and may offer promising targets for early detection and treatment. ..
  9. Borlak J, Jenke H. Cross-talk between aryl hydrocarbon receptor and mitogen-activated protein kinase signaling pathway in liver cancer through c-raf transcriptional regulation. Mol Cancer Res. 2008;6:1326-36 pubmed publisher
    ..Taken collectively, we show AhR to be a master regulator of c-raf and propose cross-talk between AhR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis. ..
  10. Piazzolla D, Meissl K, Kucerova L, Rubiolo C, Baccarini M. Raf-1 sets the threshold of Fas sensitivity by modulating Rok-alpha signaling. J Cell Biol. 2005;171:1013-22 pubmed
    ..Thus, Raf-1 has an essential function in regulating Fas expression and setting the threshold of Fas sensitivity during embryonic life. ..
  11. Garnett M, Rana S, Paterson H, Barford D, Marais R. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell. 2005;20:963-9 pubmed
    ..Thus, we have identified a B-RAF-C-RAF-MEK-ERK cascade that signals not only in cancer but also in normal cells. ..
  12. Krejci P, Masri B, Fontaine V, Mekikian P, Weis M, Prats H, et al. Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. J Cell Sci. 2005;118:5089-100 pubmed
    ..We conclude that CNP utilizes both direct and indirect ways to counteract the effects of FGF signaling in a chondrocyte environment. ..
  13. Lamberti A, Longo O, Marra M, Tagliaferri P, Bismuto E, Fiengo A, et al. C-Raf antagonizes apoptosis induced by IFN-alpha in human lung cancer cells by phosphorylation and increase of the intracellular content of elongation factor 1A. Cell Death Differ. 2007;14:952-62 pubmed
    ..The dynamic simulation of 3Dstructure of eEF-1A identified putative serine and threonine phosphorylation sites. In conclusion, the interaction between eEF-1A and C-Raf increases eEF-1A stability and induces a survival activity. ..
  14. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7:295-308 pubmed
    ..Here we will discuss the implications of germline mutations in the Ras-Raf-MEK-ERK pathway for understanding normal developmental processes and cancer pathogenesis. ..
  15. Gringhuis S, den Dunnen J, Litjens M, Van het Hof B, van Kooyk Y, Geijtenbeek T. C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB. Immunity. 2007;26:605-16 pubmed
    ..Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens. ..
  16. Ehrenreiter K, Kern F, Velamoor V, Meissl K, Galabova Kovacs G, Sibilia M, et al. Raf-1 addiction in Ras-induced skin carcinogenesis. Cancer Cell. 2009;16:149-60 pubmed publisher
    ..These data link the Raf-1:Rok-alpha complex to STAT3/Myc activation and delineate a pathway crucial for cell fate decision in Ras-induced tumorigenesis. ..
  17. Moretó J, Vidal Quadras M, Pol A, Santos E, Grewal T, Enrich C, et al. Differential involvement of H- and K-Ras in Raf-1 activation determines the role of calmodulin in MAPK signaling. Cell Signal. 2009;21:1827-36 pubmed publisher
  18. Santos S, Verveer P, Bastiaens P. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat Cell Biol. 2007;9:324-30 pubmed
    ..These results show that growth factor context determines the topology of the MAPK signalling network and that the resulting dynamics govern cell fate. ..
  19. Ceteci F, Ceteci S, Karreman C, Kramer B, Asan E, Götz R, et al. Disruption of tumor cell adhesion promotes angiogenic switch and progression to micrometastasis in RAF-driven murine lung cancer. Cancer Cell. 2007;12:145-59 pubmed
    ..In vivo, lung tumor cells with disrupted E-cadherin expressed beta-catenin target genes normally found in other endodermal lineages suggesting that reprogramming may be involved in metastatic progression. ..
  20. Moretó J, Lladó A, Vidal Quadras M, Calvo M, Pol A, Enrich C, et al. Calmodulin modulates H-Ras mediated Raf-1 activation. Cell Signal. 2008;20:1092-103 pubmed publisher
    ..Importantly, in H-Ras depleted COS-1 cells, calmodulin does not modulate MAPK activation. Altogether, the results suggest that calmodulin regulation of MAPK in COS-1 cells relies upon H-Ras control of Raf-1 activity and involves PI3K. ..
  21. Rodriguez Viciana P, Oses Prieto J, Burlingame A, Fried M, McCormick F. A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity. Mol Cell. 2006;22:217-30 pubmed
    ..We propose that the Shoc2-PP1c holoenzyme provides an attractive therapeutic target for inhibition of the MAPK pathway in cancer. ..
  22. Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature. 2009;461:542-5 pubmed publisher
    ..Together, our data identify the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis. ..
  23. Lowenberg M, Verhaar A, van den Blink B, ten Kate F, van Deventer S, Peppelenbosch M, et al. Specific inhibition of c-Raf activity by semapimod induces clinical remission in severe Crohn's disease. J Immunol. 2005;175:2293-300 pubmed
    ..Our observations indicate that c-Raf inhibitors are prime candidates for the treatment of CD. ..
  24. Baccarini M. Second nature: biological functions of the Raf-1 "kinase". FEBS Lett. 2005;579:3271-7 pubmed
    ..Do they still hold surprises? Recent gene targeting studies indicate that they do. This review focuses on the regulation and biology of the best-studied Raf isoform, Raf-1, in the context of its kinase-independent functions. ..
  25. Ehrenreiter K, Piazzolla D, Velamoor V, Sobczak I, Small J, Takeda J, et al. Raf-1 regulates Rho signaling and cell migration. J Cell Biol. 2005;168:955-64 pubmed
    ..Thus, Raf-1 plays an essential, kinase-independent function as a spatial regulator of Rho downstream signaling during migration. ..
  26. Terai K, Matsuda M. Ras binding opens c-Raf to expose the docking site for mitogen-activated protein kinase kinase. EMBO Rep. 2005;6:251-5 pubmed
    ..In contrast, the cytosolic Ras mutant significantly enhanced MEK phosphorylation by a membrane-targeted c-Raf. These results demonstrated the essential role of Ras-induced conformational change in MEK activation by c-Raf. ..
  27. Wilhelm S, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. 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. Cancer Res. 2004;64:7099-109 pubmed
    ..These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis. ..
  28. Ding Q, Gros R, Gray I, Taussig R, Ferguson S, Feldman R. Raf kinase activation of adenylyl cyclases: isoform-selective regulation. Mol Pharmacol. 2004;66:921-8 pubmed
    ..These functional interactions (as well as the physical association) between adenylyl cyclases and Raf kinases suggest an important but previously unrecognized interaction between these two key regulatory enzymes. ..
  29. Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest. 2004;114:937-43 pubmed
    ..The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism. ..
  30. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5:875-85 pubmed
  31. O Neill E, Rushworth L, Baccarini M, Kolch W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science. 2004;306:2267-70 pubmed
    ..Conversely, depletion of Raf-1 from Raf-1+/+ mouse or human cells led to MST2 activation and apoptosis. The concomitant depletion of both Raf-1 and MST2 prevented apoptosis. ..
  32. Trakul N, Menard R, Schade G, Qian Z, Rosner M. Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. J Biol Chem. 2005;280:24931-40 pubmed
    ..These results indicate that selective modulation of c-Raf-1 but not B-Raf activation by RKIP can limit the dynamic range of the MAPK signaling response to growth factors and may play a critical role in growth and development. ..
  33. Vaughan C, Mollapour M, Smith J, Truman A, Hu B, Good V, et al. Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Mol Cell. 2008;31:886-95 pubmed publisher
    ..These data reveal a cyclic regulatory mechanism for Cdc37, in which its constitutive phosphorylation is reversed by targeted dephosphorylation in Hsp90 complexes. ..
  34. Roskoski R. RAF protein-serine/threonine kinases: structure and regulation. Biochem Biophys Res Commun. 2010;399:313-7 pubmed publisher
    ..C-RAF plays a key role in this paradoxical increase in downstream MEK-ERK activation. ..
  35. Chernyavsky A, Arredondo J, Galitovskiy V, Qian J, Grando S. Upregulation of nuclear factor-kappaB expression by SLURP-1 is mediated by alpha7-nicotinic acetylcholine receptor and involves both ionic events and activation of protein kinases. Am J Physiol Cell Physiol. 2010;299:C903-11 pubmed publisher
    ..Thus, there exists a previously not appreciated network of noncanonical auto/paracrine ligands of nAChR of the Ly-6 protein family, which merits further investigations. ..
  36. Allanson J, Bohring A, Dörr H, Dufke A, Gillessen Kaesbach G, Horn D, et al. The face of Noonan syndrome: Does phenotype predict genotype. Am J Med Genet A. 2010;152A:1960-6 pubmed publisher
    ..Thus, the facial phenotype, alone, is insufficient to predict the genotype, but certain facial features may facilitate an educated guess in some cases...
  37. Kasiappan R, Shih H, Chu K, Chen W, Liu H, Huang S, et al. Loss of p53 and MCT-1 overexpression synergistically promote chromosome instability and tumorigenicity. Mol Cancer Res. 2009;7:536-48 pubmed publisher
    ..Our results indicate that synergistic promotions of chromosomal imbalances and oncogenic potency as a result of MCT-1 expression and p53 loss play important roles in tumor development. ..
  38. Kuo T. The influence of methylmercury on the nitric oxide production of alveolar macrophages. Toxicol Ind Health. 2008;24:531-8 pubmed publisher
    ..We discovered that methylmercury could activate protein kinase A, which in turn would inhibit the activation of Raf-1-ERK and so inhibit the release of nitric oxide. ..
  39. Ibiza S, Pérez Rodríguez A, Ortega A, Martínez Ruiz A, Barreiro O, García Domínguez C, et al. Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells. Proc Natl Acad Sci U S A. 2008;105:10507-12 pubmed publisher
    ..Our data define a signaling mechanism for the regulation of the Ras/ERK pathway based on the eNOS-dependent differential activation of N-Ras and K-Ras at specific cell compartments. ..
  40. Kim Y, Suarez J, Hu Y, McDonough P, Boer C, Dix D, et al. Deletion of the inducible 70-kDa heat shock protein genes in mice impairs cardiac contractile function and calcium handling associated with hypertrophy. Circulation. 2006;113:2589-97 pubmed
    ..In addition, deletion of Hsp70 genes might induce cardiac dysfunction and development of cardiac hypertrophy through the activation of JNK, p38-MAPK, Raf-1, and ERK. ..
  41. Adnane L, Trail P, Taylor I, Wilhelm S. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612 pubmed
    ..This agent is currently being evaluated in phase III clinical trials in renal cell and hepatocellular carcinomas. ..
  42. Shan L, Zhang R, Zhang W, Lee E, Sridhar R, Snyderwine E, et al. Image-based evaluation of the molecular events underlying HC11 mammary epithelial cell differentiation. Anal Biochem. 2008;382:122-8 pubmed publisher
    ..It can be adopted for high-throughput screening of small molecules for their effects on mammary epithelial cell growth, differentiation, and carcinogenesis. ..
  43. Das A, Banik N, Ray S. Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis. Neurochem Res. 2007;32:2167-83 pubmed
    ..This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma. ..
  44. Li H, Lu T, Zhu T, Jiang Y, Rao S, Hu L, et al. Virtual screening for Raf-1 kinase inhibitors based on pharmacophore model of substituted ureas. Eur J Med Chem. 2009;44:1240-9 pubmed publisher
    ..The study may facilitate the discovery and rational design of novel leads with potent inhibitory activity targeting Raf-1 kinase. ..
  45. Reid D, Gow N, Brown G. Pattern recognition: recent insights from Dectin-1. Curr Opin Immunol. 2009;21:30-7 pubmed publisher
    ..Recent studies have highlighted the importance of Dectin-1 in anti-fungal immunity, in both mice and humans, and have suggested a possible involvement of this receptor in the control of mycobacterial infections. ..
  46. Zhang Q, Adiseshaiah P, Kalvakolanu D, Reddy S. A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression. J Biol Chem. 2006;281:10174-81 pubmed
  47. Lin L, Su Z, Lebedeva I, Gupta P, Boukerche H, Rai T, et al. Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis. Cell Death Differ. 2006;13:1982-93 pubmed
  48. Jilaveanu L, Zito C, Aziz S, Conrad P, Schmitz J, Sznol M, et al. C-Raf is associated with disease progression and cell proliferation in a subset of melanomas. Clin Cancer Res. 2009;15:5704-13 pubmed publisher
    ..C-Raf expression is up-regulated in a subset of melanomas but not in nevi, suggesting that it might be a valuable diagnostic marker and therapeutic target. ..
  49. Kunnimalaiyaan M, Ndiaye M, Chen H. Neuroendocrine tumor cell growth inhibition by ZM336372 through alterations in multiple signaling pathways. Surgery. 2007;142:959-64; discussion 959-64 pubmed
    ..This is the first description of a novel compound ZM336372 that regulates multiple pathways in NEN cells. ..
  50. Fauti T, Müller Brüsselbach S, Kreutzer M, Rieck M, Meissner W, Rapp U, et al. Induction of PPARbeta and prostacyclin (PGI2) synthesis by Raf signaling: failure of PGI2 to activate PPARbeta. FEBS J. 2006;273:170-9 pubmed
    ..Our data obtained with four different cell types and different experimental strategies do not support the prevailing opinion that PGI2 plays a significant role in the regulation of PPARbeta. ..
  51. Pan M, Chang H, Hung W. Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases. Cell Signal. 2008;20:1134-41 pubmed publisher
    ..Taken together, we conclude that NS398 and other NSAIDs act via inhibition of Ras/c-Raf interaction and up-regulation of MKPs to suppress the ERK-mediated signaling. ..
  52. Hanai Y, Tokuda H, Takai S, Harada A, Ohta T, Kozawa O. Minodronate suppresses prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. Horm Metab Res. 2006;38:152-8 pubmed
    ..Taken together, these results indicate that minodronate suppresses PGF2alpha-stimulated VEGF synthesis at the point between PKC and Raf-1 in osteoblasts. ..
  53. Noser J, Mael A, Sakuma R, Ohmine S, Marcato P, Lee P, et al. The RAS/Raf1/MEK/ERK signaling pathway facilitates VSV-mediated oncolysis: implication for the defective interferon response in cancer cells. Mol Ther. 2007;15:1531-6 pubmed
    ..In view of the fact that 30% of all cancers have constitutive activation of the RAS/Raf1/MEK/ERK pathway, VSV would be an ideal oncolytic virus for targeting such cancers. ..