raf kinases

Summary

Summary: A family of closely-related serine-threonine kinases that were originally identified as the cellular homologs of the retrovirus-derived V-RAF KINASES. They are MAP kinase kinase kinases that play important roles in SIGNAL TRANSDUCTION.

Top Publications

  1. Poulikakos P, Zhang C, Bollag G, Shokat K, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427-30 pubmed publisher
    ..In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS. ..
  2. Wimmer R, Baccarini M. Partner exchange: protein-protein interactions in the Raf pathway. Trends Biochem Sci. 2010;35:660-8 pubmed publisher
    ..Given the roles of these interactions in tumorigenesis, their study will provide new opportunities for molecule-based therapies that target the pathway. ..
  3. McCubrey J, Milella M, Tafuri A, Martelli A, Lunghi P, Bonati A, et al. Targeting the Raf/MEK/ERK pathway with small-molecule inhibitors. Curr Opin Investig Drugs. 2008;9:614-30 pubmed
    ..The effective targeting of this pathway may result in the suppression of cell growth, and death of malignant cells. This review focuses on targeting the Raf/MEK/ERK pathway with small-molecule inhibitors for the treatment of cancer. ..
  4. Granovsky A, Clark M, McElheny D, Heil G, Hong J, Liu X, et al. Raf kinase inhibitory protein function is regulated via a flexible pocket and novel phosphorylation-dependent mechanism. Mol Cell Biol. 2009;29:1306-20 pubmed publisher
    ..This mechanism is an example of an emerging theme involving the regulation of signaling proteins and their interaction with effectors at the level of protein dynamics. ..
  5. Lefloch R, Pouyssegur J, Lenormand P. Total ERK1/2 activity regulates cell proliferation. Cell Cycle. 2009;8:705-11 pubmed
    ..After integrating signals from Ras, Raf and MEK isoforms, ERK1 and ERK2 regulate positively cell proliferation according to their expression levels. ..
  6. Lyne P, Aquila B, Cook D, Dakin L, Ezhuthachan J, Ioannidis S, et al. Identification of amidoheteroaryls as potent inhibitors of mutant (V600E) B-Raf kinase with in vivo activity. Bioorg Med Chem Lett. 2009;19:1026-9 pubmed publisher
    ..Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice. ..
  7. Menges C, McCance D. Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA2 receptor. Oncogene. 2008;27:2934-40 pubmed
  8. Xing F, Persaud Y, Pratilas C, Taylor B, Janakiraman M, She Q, et al. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene. 2012;31:446-57 pubmed publisher
  9. Corcoran R, Ebi H, Turke A, Coffee E, Nishino M, Cogdill A, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227-35 pubmed publisher

More Information

Publications62

  1. Lv C, Sun W, Sun H, Wei S, Chen R, Wang B, et al. Asperolide A, a marine-derived tetranorditerpenoid, induces G2/M arrest in human NCI-H460 lung carcinoma cells, is mediated by p53-p21 stabilization and modulated by Ras/Raf/MEK/ERK signaling pathway. Mar Drugs. 2013;11:316-31 pubmed publisher
    ..Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies...
  2. Aplin A, Kaplan F, Shao Y. Mechanisms of resistance to RAF inhibitors in melanoma. J Invest Dermatol. 2011;131:1817-20 pubmed publisher
    ..Bi-directional translational efforts are now essential to determine the mechanisms underlying acquired/secondary and intrinsic resistance to RAF inhibitors. ..
  3. Steelman L, Chappell W, Abrams S, Kempf R, Long J, Laidler P, et al. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY). 2011;3:192-222 pubmed
    ..Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health. ..
  4. Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-90 pubmed publisher
    ..ClinicalTrials.gov number, NCT00105443.) ..
  5. Villanueva J, Vultur A, Lee J, Somasundaram R, Fukunaga Kalabis M, Cipolla A, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18:683-95 pubmed publisher
    ..Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors. ..
  6. Lu X, Tang X, Guo W, Ren T, Zhao H. Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway. J Surg Oncol. 2010;102:821-6 pubmed publisher
  7. Lo H. Targeting Ras-RAF-ERK and its interactive pathways as a novel therapy for malignant gliomas. Curr Cancer Drug Targets. 2010;10:840-8 pubmed
  8. Friday B, Yu C, Dy G, Smith P, Wang L, Thibodeau S, et al. BRAF V600E disrupts AZD6244-induced abrogation of negative feedback pathways between extracellular signal-regulated kinase and Raf proteins. Cancer Res. 2008;68:6145-53 pubmed publisher
    ..These data suggest an approach to identifying cells that may be sensitive to AZD6244 and other MEK inhibitors. ..
  9. Santarpia L, Lippman S, El Naggar A. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-19 pubmed publisher
    ..Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects...
  10. Hatzivassiliou G, Song K, Yen I, Brandhuber B, Anderson D, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431-5 pubmed publisher
    ..Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors...
  11. Smolen P, Baxter D, Byrne J. Bistable MAP kinase activity: a plausible mechanism contributing to maintenance of late long-term potentiation. Am J Physiol Cell Physiol. 2008;294:C503-15 pubmed
    ..Experiments using a fluorescent MAPK substrate may further test this hypothesis. ..
  12. Polzien L, Benz R, Rapp U. Can BAD pores be good? New insights from examining BAD as a target of RAF kinases. Adv Enzyme Regul. 2010;50:147-59 pubmed publisher
  13. McCubrey J, Abrams S, Ligresti G, Misaghian N, Wong E, Steelman L, et al. Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance. Leukemia. 2008;22:2080-90 pubmed publisher
    ..Thus the p53 and Raf/MEK/ERK pathways play key roles in drug sensitivity. Targeting these pathways may be effective in certain drug-resistant leukemias that are WT at p53. ..
  14. Abrams S, Steelman L, Shelton J, Wong E, Chappell W, Basecke J, et al. The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle. 2010;9:1781-91 pubmed
    ..These results indicate that targeting the Raf/MEK/ERK and PI3K/Akt/mTOR pathways may be an effective approach for therapeutic intervention in drug resistant cancers that have mutations activating these cascades. ..
  15. Rodt T, von Falck C, Halter R, Ringe K, Shin H, Galanski M, et al. In vivo microCT quantification of lung tumor growth in SPC-raf transgenic mice. Front Biosci (Landmark Ed). 2009;14:1939-44 pubmed
    ..The imaging algorithm allows in vivo quantification of lung tumor load and tumor growth in transgenic mice with an acceptable intra- and interobserver variability. ..
  16. Niault T, Baccarini M. Targets of Raf in tumorigenesis. Carcinogenesis. 2010;31:1165-74 pubmed publisher
    ..This review focuses on old and new targets of Raf in tumorigenesis. ..
  17. Fischer A, Baljuls A, Reinders J, Nekhoroshkova E, Sibilski C, Metz R, et al. Regulation of RAF activity by 14-3-3 proteins: RAF kinases associate functionally with both homo- and heterodimeric forms of 14-3-3 proteins. J Biol Chem. 2009;284:3183-94 pubmed publisher
    Mammalian 14-3-3 proteins play a crucial role in the activation process of RAF kinases. However, little is known about the selectivity of the mammalian 14-3-3 isoforms with respect to RAF association and activation...
  18. Hashimoto K, Ishima T. A novel target of action of minocycline in NGF-induced neurite outgrowth in PC12 cells: translation initiation [corrected] factor eIF4AI. PLoS ONE. 2010;5:e15430 pubmed publisher
    ..These findings suggest that eIF4AI might play a role in the novel mechanism of minocycline. Therefore, agents that can increase eIF4AI protein would be novel therapeutic drugs for certain neurodegenerative and psychiatric diseases. ..
  19. Gedaly R, Angulo P, Hundley J, Daily M, Chen C, Koch A, et al. PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010;30:4951-8 pubmed
    ..The combination of sorafenib and PI-103 can significantly inhibit EGF-stimulated Huh7 proliferation by blocking both Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. ..
  20. Cao L, Xu C, Zhang Y, Cao Y, Edvinsson L. Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors. BMC Neurosci. 2011;12:109 pubmed publisher
    ..SHS upregulates cerebrovascular ETA receptors via the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke. ..
  21. Zhang Z, Miao L, Lv C, Sun H, Wei S, Wang B, et al. Wentilactone B induces G2/M phase arrest and apoptosis via the Ras/Raf/MAPK signaling pathway in human hepatoma SMMC-7721 cells. Cell Death Dis. 2013;4:e657 pubmed publisher
  22. Zeng L, Imamoto A, Rosner M. Raf kinase inhibitory protein (RKIP): a physiological regulator and future therapeutic target. Expert Opin Ther Targets. 2008;12:1275-87 pubmed
    ..Emerging evidence suggests that RKIP is implicated in several human diseases or disorders, among them metastatic tumorigenesis and Alzheimer's disease. ..
  23. Abel E, Basile K, Kugel C, Witkiewicz A, Le K, Amaravadi R, et al. Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J Clin Invest. 2013;123:2155-68 pubmed publisher
  24. Hausott B, Vallant N, Auer M, Yang L, Dai F, Brand Saberi B, et al. Sprouty2 down-regulation promotes axon growth by adult sensory neurons. Mol Cell Neurosci. 2009;42:328-40 pubmed publisher
    ..Together, our results imply that Sprouty2 is highly expressed in adult peripheral neurons and its down-regulation strongly promotes elongative axon growth by activation of the Ras/Raf/ERK pathway. ..
  25. Du K, Zheng Q, Zhou M, Zhu L, Ai B, Zhou L. Chlamydial antiapoptotic activity involves activation of the Raf/MEK/ERK survival pathway. Curr Microbiol. 2011;63:341-6 pubmed publisher
    ..Inhibition of the pathway sensitized Chlamydia-infected cells to STS-mediated cell apoptosis. The data indicate that chlamydial antiapoptotic activity involves activation of the Raf/MEK/ERK survival pathway. ..
  26. McKay M, Ritt D, Morrison D. RAF inhibitor-induced KSR1/B-RAF binding and its effects on ERK cascade signaling. Curr Biol. 2011;21:563-8 pubmed publisher
    ..Strikingly, we find that KSR1 competes with C-RAF for inhibitor-induced binding to B-RAF and, as a result, alters the effect of the inhibitors on ERK cascade signaling. ..
  27. Chappell W, Steelman L, Long J, Kempf R, Abrams S, Franklin R, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011;2:135-64 pubmed
    ..Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging. ..
  28. McCubrey J, Steelman L, Kempf C, Chappell W, Abrams S, Stivala F, et al. Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. J Cell Physiol. 2011;226:2762-81 pubmed publisher
    ..Controlling the expression of these pathways could improve cancer therapy and ameliorate human health. ..
  29. Kern F, Niault T, Baccarini M. Ras and Raf pathways in epidermis development and carcinogenesis. Br J Cancer. 2011;104:229-34 pubmed publisher
    ..In particular, we will focus on the recently established role of Raf-1 as the decisive element that, by restraining keratinocyte differentiation, allows the development and maintenance of Ras-driven tumours. ..
  30. Yaari S, Jacob Hirsch J, Amariglio N, Haklai R, Rechavi G, Kloog Y. Disruption of cooperation between Ras and MycN in human neuroblastoma cells promotes growth arrest. Clin Cancer Res. 2005;11:4321-30 pubmed
    ..Ras inhibitors are therefore likely candidates for the treatment of advanced neuroblastoma characterized by high expression of MycN. ..
  31. Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24:21-44 pubmed
    ..Although the main core phosphorylation chain of the cascade includes Raf kinases, MEK1/2, ERK1/2 (ERKs) and RSKs, other alternatively spliced forms and distinct components exist in the ..
  32. Ouyang B, Knauf J, Smith E, Zhang L, Ramsey T, Yusuff N, et al. Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res. 2006;12:1785-93 pubmed
    ..Compounds that inhibit kinase activity are effective growth inhibitors for poorly differentiated thyroid cancer cell lines with either RET or RAF mutations, and hold promise for treatment of most forms of papillary thyroid carcinoma. ..
  33. Mishra S, Smolik S, Forte M, Stork P. Ras-independent activation of ERK signaling via the torso receptor tyrosine kinase is mediated by Rap1. Curr Biol. 2005;15:366-70 pubmed
    ..These studies provide the first direct genetic evidence of Rap1-mediated activation of the MAP kinase cascade in eukaryotic organisms. ..
  34. Rajalingam K, Wunder C, Brinkmann V, Churin Y, Hekman M, Sievers C, et al. Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration. Nat Cell Biol. 2005;7:837-43 pubmed
    ..Our data show an unexpected role of prohibitin in the activation of the Ras-Raf signalling pathway and in modulating epithelial cell adhesion and migration. ..
  35. Schreck R, Rapp U. Raf kinases: oncogenesis and drug discovery. Int J Cancer. 2006;119:2261-71 pubmed
  36. Leicht D, Balan V, Kaplun A, Singh Gupta V, Kaplun L, Dobson M, et al. Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta. 2007;1773:1196-212 pubmed
    ..In this review, we focus on the physiological roles of Raf kinases in normal and disease conditions, specifically cancer, and the current thoughts on Raf regulation.
  37. Benvenuti S, Sartore Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643-8 pubmed
    ..They also provide the rationale for combination therapies, targeted simultaneously to the EGFR and RAS/RAF/MAPK signaling pathways in CRC patients. ..
  38. Eves E, Shapiro P, Naik K, Klein U, Trakul N, Rosner M. Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell. 2006;23:561-74 pubmed
  39. Kyriakis J. The integration of signaling by multiprotein complexes containing Raf kinases. Biochim Biophys Acta. 2007;1773:1238-47 pubmed
    ..This review will focus on two signal integrating multiprotein complexes that involve Raf family kinases: the MLK3-B-Raf-Raf-1 complex and the Raf-1-Mst-2 complex. ..
  40. Konecny G, Pegram M, Venkatesan N, Finn R, Yang G, Rahmeh M, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630-9 pubmed
    ..These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab. ..
  41. Hjelmeland A, Lattimore K, Fee B, Shi Q, Wickman S, Keir S, et al. The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion. Mol Cancer Ther. 2007;6:2449-57 pubmed
    ..These data suggest that the combination of LBT613 and RAD001 reduces glioma cell proliferation and invasion and support examination of the combination of RAF and TOR inhibitors for the treatment of human glioblastoma patients. ..
  42. Tian T, Harding A, Inder K, Plowman S, Parton R, Hancock J. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nat Cell Biol. 2007;9:905-14 pubmed
    ..A requirement for high-fidelity signalling may explain the non-random distribution of other plasma membrane signalling complexes. ..
  43. Roy S, Plowman S, Rotblat B, Prior I, Muncke C, Grainger S, et al. Individual palmitoyl residues serve distinct roles in H-ras trafficking, microlocalization, and signaling. Mol Cell Biol. 2005;25:6722-33 pubmed
    ..Finally we show that the plasma membrane affinity of monopalmitoylated anchors is absolutely dependent on cholesterol, identifying a new role for cholesterol in promoting interactions with the raft and nonraft plasma membrane. ..
  44. Rapp U, Fischer A, Rennefahrt U, Hekman M, Albert S. BAD association with membranes is regulated by Raf kinases and association with 14-3-3 proteins. Adv Enzyme Regul. 2007;47:281-5 pubmed
  45. Zebisch A, Troppmair J. Back to the roots: the remarkable RAF oncogene story. Cell Mol Life Sci. 2006;63:1314-30 pubmed
    b>RAF kinases entered the limelight when our understanding of the genetic nature of cancer was much less defined and the seminal importance of proto-oncogenes as components of intracellular signaling pathways was just beginning to be ..
  46. Ritt D, Daar I, Morrison D. KSR regulation of the Raf-MEK-ERK cascade. Methods Enzymol. 2006;407:224-37 pubmed
    ..In this chapter, we will describe methods for assessing KSR function in response to Ras pathway activation. Protocols will be included that examine the ERK scaffolding activity and subcellular localization of KSR. ..
  47. Galabova Kovacs G, Kolbus A, Matzen D, Meissl K, Piazzolla D, Rubiolo C, et al. ERK and beyond: insights from B-Raf and Raf-1 conditional knockouts. Cell Cycle. 2006;5:1514-8 pubmed
    ..Here, we discuss some of the surprises yielded by the analysis of the role of B-Raf and Raf-1 and of their downstream effectors. ..
  48. McCubrey J, Steelman L, Chappell W, Abrams S, Wong E, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773:1263-84 pubmed
  49. Espinosa A, Porchia L, Ringel M. Targeting BRAF in thyroid cancer. Br J Cancer. 2007;96:16-20 pubmed
    ..BRAF and other RAF kinases are frequently activated by other thyroid oncogenes and are important mediators of their biological effects ..
  50. Panka D, Wang W, Atkins M, Mier J. The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells. Cancer Res. 2006;66:1611-9 pubmed
    ..These data indicate that in sensitive cell lines, BAY 43-9006-induced apoptosis is independent of Bad dephosphorylation and caspase activation and largely mediated through the nuclear translocation of AIF. ..
  51. Courtois Cox S, Genther Williams S, Reczek E, Johnson B, McGillicuddy L, Johannessen C, et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006;10:459-72 pubmed
    ..Thus, the ultimate response to the aberrant activation of the Ras pathway is a multifaceted negative feedback signaling network that terminates the oncogenic signal and participates in the senescence response. ..
  52. Zhong J, Li X, McNamee C, Chen A, Baccarini M, Snider W. Raf kinase signaling functions in sensory neuron differentiation and axon growth in vivo. Nat Neurosci. 2007;10:598-607 pubmed
    ..We conclude that Raf function is crucial for several aspects of DRG neuron development, including differentiation and axon growth. ..
  53. Beeram M, Patnaik A, Rowinsky E. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005;23:6771-90 pubmed