Gene Symbol: Raf-1
Description: Raf-1 proto-oncogene, serine/threonine kinase
Alias: CMD1NN, CRAF, NS5, Raf-1, c-Raf, RAF proto-oncogene serine/threonine-protein kinase, C-Raf proto-oncogene, serine/threonine kinase, Oncogene RAF1, proto-oncogene c-RAF, raf proto-oncogene serine/threonine protein kinase, v-raf-1 murine leukemia viral oncogene homolog 1, v-raf-1 murine leukemia viral oncogene-like protein 1
Species: human
Products:     Raf-1

Top Publications

  1. Alavi A, Hood J, Frausto R, Stupack D, Cheresh D. Role of Raf in vascular protection from distinct apoptotic stimuli. Science. 2003;301:94-6 pubmed
    ..These findings implicate Raf-1 as a pivotal regulator of endothelial cell survival during angiogenesis. ..
  2. Zha J, Harada H, Yang E, Jockel J, Korsmeyer S. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell. 1996;87:619-28 pubmed
    ..The rapid phosphorylation of BAD following IL-3 connects a proximal survival signal with the BCL-2 family, modulating this checkpoint for apoptosis. ..
  3. 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. ..
  4. Johnson S, Winner D, Wang X. Ran binding protein 9 interacts with Raf kinase but does not contribute to downstream ERK1/2 activation in skeletal myoblasts. Biochem Biophys Res Commun. 2006;340:409-16 pubmed
    ..Knockdown of RanBP9 expression did not restore the differentiation program to Raf-expressing myoblasts. Thus, RanBP9 physically associates with Raf but does not substantially contribute to the inhibitory actions of the kinase...
  5. 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
    ..We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells...
  6. Mason C, Springer C, Cooper R, Superti Furga G, Marshall C, Marais R. Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J. 1999;18:2137-48 pubmed
    ..Thus, there are considerable differences between the activation of the Raf proteins; Ras-GTP mediates two phosphorylation events required for Raf-1 activation but does not regulate such events for B-Raf. ..
  7. Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, et al. Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature. 1993;364:249-52 pubmed
    ..Consistent with such a direct interaction is the observation that Raf-1 and PKC alpha cooperate in the transformation of NIH3T3 cells. The Ser499 phosphorylation site is necessary for this synergism. ..
  8. Wan P, Garnett M, Roe S, Lee S, Niculescu Duvaz D, Good V, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-67 pubmed
    ..The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism. ..
  9. Xiang X, Zang M, Waelde C, Wen R, Luo Z. Phosphorylation of 338SSYY341 regulates specific interaction between Raf-1 and MEK1. J Biol Chem. 2002;277:44996-5003 pubmed
    ..As a result, these two sites coordinate to form a high affinity MEK-binding epitope, leading to a marked increase in Raf kinase activity. ..

More Information


  1. Akula S, Ford P, Whitman A, Hamden K, Shelton J, McCubrey J. Raf promotes human herpesvirus-8 (HHV-8/KSHV) infection. Oncogene. 2004;23:5227-41 pubmed
    ..Here we report Raf expression to significantly enhance HHV-8 infection of target cells. These findings implicate a role for Raf not only in the infectious entry of HHV-8 but also in modulating KS pathogenesis. ..
  2. Zhang L, Wang H, Liu D, Liddington R, Fu H. Raf-1 kinase and exoenzyme S interact with 14-3-3zeta through a common site involving lysine 49. J Biol Chem. 1997;272:13717-24 pubmed
    ..The parallel effects of this single point mutation on both Raf-1 binding and ExoS activation strongly suggest that diverse associated proteins share a common structural binding determinant on 14-3-3zeta. ..
  3. Ren G, Liu X, Mao X, Zhang Y, Stankiewicz E, Hylands L, et al. Identification of frequent BRAF copy number gain and alterations of RAF genes in Chinese prostate cancer. Genes Chromosomes Cancer. 2012;51:1014-23 pubmed publisher
    ..Our finding suggests that the activation of the RAS/RAF/MEK/ERK pathway may be frequent in Chinese prostate cancer, with RAF gene copy number gain potentially being the main contributor. ..
  4. Polzien L, Baljuls A, Rennefahrt U, Fischer A, Schmitz W, Zahedi R, et al. Identification of novel in vivo phosphorylation sites of the human proapoptotic protein BAD: pore-forming activity of BAD is regulated by phosphorylation. J Biol Chem. 2009;284:28004-20 pubmed publisher
    ..This pore-forming capacity was dependent on phosphorylation status and interaction with 14-3-3 proteins. Collectively, our findings provide new insights into the regulation of BAD function by phosphorylation. ..
  5. Wang H, Takayama S, Rapp U, Reed J. Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. Proc Natl Acad Sci U S A. 1996;93:7063-8 pubmed
    ..BAG-1 also activates this mammalian kinase in yeast. These observations suggest that the Bcl-2 binding protein BAG-1 joins Ras and 14-3-3 proteins as potential activators of the kinase Raf-1. ..
  6. Gringhuis S, den Dunnen J, Litjens M, van der Vlist M, Geijtenbeek T. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol. 2009;10:1081-8 pubmed publisher
    ..Our study reveals another level of plasticity in tailoring adaptive immunity to pathogens. ..
  7. 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
    ..Upon treatment with the CRAF inhibitor sorafenib, these lines underwent apoptosis and associated with mitochondrial depolarization and ..
  8. Wu X, Carr H, Dan I, Ruvolo P, Frost J. p21 activated kinase 5 activates Raf-1 and targets it to mitochondria. J Cell Biochem. 2008;105:167-75 pubmed publisher
    ..These data indicate that PAK5 is a potent regulator of Raf-1 activity and may control Raf-1 dependent signaling at mitochondria. ..
  9. Fischer A, Hekman M, Kuhlmann J, Rubio I, Wiese S, Rapp U. B- and C-RAF display essential differences in their binding to Ras: the isotype-specific N terminus of B-RAF facilitates Ras binding. J Biol Chem. 2007;282:26503-16 pubmed
    ..Taken together, these data suggest that the activation of B-RAF, in contrast to C-RAF, may take place both at the plasma membrane and in the cytosolic environment. ..
  10. Steelman L, Abrams S, Shelton J, Chappell W, Basecke J, Stivala F, et al. Dominant roles of the Raf/MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs. Cell Cycle. 2010;9:1629-38 pubmed
    ..Targeting the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways may be an effective approach for therapeutic intervention in those cancers which have upstream mutations which result in activation of these pathways. ..
  11. Weber C, Slupsky J, Kalmes H, Rapp U. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 2001;61:3595-8 pubmed
    ..Within the mechanism of Raf activation, two isoforms of Raf, cRaf and BRaf, may cooperate...
  12. Morrison D, Heidecker G, Rapp U, Copeland T. Identification of the major phosphorylation sites of the Raf-1 kinase. J Biol Chem. 1993;268:17309-16 pubmed
    ..Interestingly, these RSXSXP sequences are completely conserved throughout evolution in all Raf family members. ..
  13. Blasco R, Francoz S, Santamaria D, Canamero M, Dubus P, Charron J, et al. c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. Cancer Cell. 2011;19:652-63 pubmed publisher
    ..These results indicate that c-Raf plays a unique role in mediating K-Ras signaling and makes it a suitable target for therapeutic intervention. ..
  14. 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. ..
  15. Chong H, Guan K. Regulation of Raf through phosphorylation and N terminus-C terminus interaction. J Biol Chem. 2003;278:36269-76 pubmed
    ..These data demonstrate that N-terminal domain binding to the kinase domain inhibits the activity of the kinase domain. However, this inhibition is relieved when the C-terminal kinase domain is activated by phosphorylation. ..
  16. 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. ..
  17. King A, Sun H, Diaz B, Barnard D, Miao W, Bagrodia S, et al. The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature. 1998;396:180-3 pubmed
    ..As guanine-nucleotide-exchange activity on Rac can be stimulated by a Ras-dependent phosphatidylinositol-3-OH kinase, a mechanism could exist through which one Ras effector pathway can be influenced by another. ..
  18. Li W, Han M, Guan K. The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. Genes Dev. 2000;14:895-900 pubmed
    ..Sur-8 interacts with Ras and Raf and is able to form a ternary complex with the two proteins. Thus, Sur-8 may function as a scaffold that enhances Ras-MAP kinase signal transduction by facilitating the interaction between Ras and Raf. ..
  19. Demand J, Alberti S, Patterson C, Hohfeld J. Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol. 2001;11:1569-77 pubmed
    ..The chaperone cofactors thus act as key regulators to influence protein quality control. ..
  20. Villalonga P, López Alcalá C, Bosch M, Chiloeches A, Rocamora N, Gil J, et al. Calmodulin binds to K-Ras, but not to H- or N-Ras, and modulates its downstream signaling. Mol Cell Biol. 2001;21:7345-54 pubmed
    ..Thus, GTP-bound K-RasB is a calmodulin-binding protein, and we suggest that this binding may be a key element in the modulation of Ras signaling. ..
  21. Greenway A, Holloway G, McPhee D, Ellis P, Cornall A, Lidman M. HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication. J Biosci. 2003;28:323-35 pubmed
  22. Heidorn S, Milagre C, Whittaker S, Nourry A, Niculescu Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209-21 pubmed publisher
    ..We show that drugs that selectively inhibit BRAF drive RAS-dependent BRAF binding to CRAF, CRAF activation, and MEK-ERK signaling...
  23. Sato S, Trackman P, Maki J, Myllyharju J, Kirsch K, Sonenshein G. The Ras signaling inhibitor LOX-PP interacts with Hsp70 and c-Raf to reduce Erk activation and transformed phenotype of breast cancer cells. Mol Cell Biol. 2011;31:2683-95 pubmed publisher
    ..Thus, the interaction of LOX-PP with Hsp70 and c-Raf inhibits a critical intermediate in Ras-induced MEK signaling and plays an important role in the function of this tumor suppressor. ..
  24. Jin S, Zhuo Y, Guo W, Field J. p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association. J Biol Chem. 2005;280:24698-705 pubmed
    ..These signals are specific for Pak1, because Src-activated Raf-1 only stimulates the MAP kinase cascade. Thus, our data identify the molecular connections of a Pak1-Raf-1-BAD pathway that is involved in cell survival signaling. ..
  25. 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. ..
  26. Song J, Takeda M, Morimoto R. Bag1-Hsp70 mediates a physiological stress signalling pathway that regulates Raf-1/ERK and cell growth. Nat Cell Biol. 2001;3:276-82 pubmed
    ..We propose that Bag1 functions in the heat-shock response to coordinate cell growth signals and mitogenesis, and that Hsp70 functions as a sensor in stress signalling. ..
  27. 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...
  28. Tzivion G, Luo Z, Avruch J. Calyculin A-induced vimentin phosphorylation sequesters 14-3-3 and displaces other 14-3-3 partners in vivo. J Biol Chem. 2000;275:29772-8 pubmed
    ..Thus, phosphovimentin, by sequestering 14-3-3 and limiting its availability to other target proteins can affect intracellular signaling processes that require 14-3-3. ..
  29. Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, et al. Raf family kinases: old dogs have learned new tricks. Genes Cancer. 2011;2:232-60 pubmed publisher
    ..Finally, we also argue for the necessity of more systemic approaches to obtain a better understanding of how the Ras-Raf signaling network generates biological specificity. ..
  30. 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. ..
  31. Chong H, Lee J, Guan K. Positive and negative regulation of Raf kinase activity and function by phosphorylation. EMBO J. 2001;20:3716-27 pubmed
    ..elegans. Our results demonstrate that different members of the Raf family kinases have both common and distinct phosphorylation mechanisms to regulate kinase activity and biological function. ..
  32. Wang H, Rapp U, Reed J. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell. 1996;87:629-38 pubmed
    ..Bcl-2 can therefore target Raf-1 to mitochondrial membranes, allowing this kinase to phosphorylate BAD or possibly other protein substrates involved in apoptosis regulation. ..
  33. Schulte S, Waha A, Steiger B, Denkhaus D, Dörner E, Calaminus G, et al. CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways. Oncotarget. 2016;7:55026-55042 pubmed publisher
    ..In addition, mutational activation of Kit-, Ras/Raf/Erk- and Akt- pathways indicate the biological importance of these pathways and their components as potential targets for therapy. ..
  34. Chai J, Wang S, Han D, Dong W, Xie C, Guo H. MicroRNA-455 inhibits proliferation and invasion of colorectal cancer by targeting RAF proto-oncogene serine/threonine-protein kinase. Tumour Biol. 2015;36:1313-21 pubmed publisher
    ..Collectively, our study demonstrated that miR-455-RAF1 may represent a new potential therapeutic target for colorectal carcinoma treatment. ..
  35. Corrado A, Ferrari S, Politti U, Mazzi V, Miccoli M, Materazzi G, et al. Aggressive thyroid cancer: targeted therapy with sorafenib. Minerva Endocrinol. 2017;42:64-76 pubmed publisher
    ..Currently, USA Food and Drug Administration has approved the use of sorafenib for metastatic differentiated thyroid cancer. ..
  36. Zhang N, Lu C, Chen L. miR-217 regulates tumor growth and apoptosis by targeting the MAPK signaling pathway in colorectal cancer. Oncol Lett. 2016;12:4589-4597 pubmed publisher
    ..These results indicate that miR-217 is a promising therapeutic target for the treatment of CRC. ..
  37. Hong S, Kim J, Lin M, Park J. The Raf/MEK/extracellular signal-regulated kinase 1/2 pathway can mediate growth inhibitory and differentiation signaling via androgen receptor downregulation in prostate cancer cells. Exp Cell Res. 2011;317:2671-82 pubmed publisher
    ..Our study demonstrates a novel role of the Raf/MEK/ERK pathway in regulating AR expression in certain PCa types and provides an insight into PCa responses to its aberrant activation. ..
  38. Li M, Ong S, Rajwa B, Thieu V, Geahlen R, Harrison M. The SH3 domain of Lck modulates T-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of Raf-1. Mol Cell Biol. 2008;28:630-41 pubmed
    ..Our results support a model where under conditions of weak stimulation through the TCR, in addition to activated Ras, Golgi apparatus-localized Lck is needed for the full activation of Raf-1. ..
  39. Wu Z, Fu C, Shi L, Ruan L, Lin D, Guo C. Structural basis for RKIP binding with its substrate Raf1 kinase. Biotechnol Lett. 2014;36:1869-74 pubmed publisher
    ..46 mM(-1). Our results provide important structural clues for designing the lead compound that disrupts RKIP-Raf1 interaction. ..
  40. 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. ..
  41. Marquette A, Andre J, Bagot M, Bensussan A, Dumaz N. ERK and PDE4 cooperate to induce RAF isoform switching in melanoma. Nat Struct Mol Biol. 2011;18:584-91 pubmed publisher
    Melanocytes use BRAF to activate the MAP kinase (MAPK) pathway because CRAF is inhibited by the cyclic AMP (cAMP) pathway in these cells. By contrast, melanomas harboring Ras mutations use CRAF to activate the MAPK pathway...
  42. Zhao Y, Chu X, Chen J, Wang Y, Gao S, Jiang Y, et al. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat Commun. 2016;7:12368 pubmed publisher
    ..Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications. ..
  43. Lu G, Gong P. A structural view of the RNA-dependent RNA polymerases from the Flavivirus genus. Virus Res. 2017;234:34-43 pubmed publisher
    ..is naturally fused to a methyltransferase (MTase), and the full-length protein is named nonstructural protein 5 (NS5)...
  44. Huang Y, Zang M, Xiong W, Luo Z, Mei L. Erbin suppresses the MAP kinase pathway. J Biol Chem. 2003;278:1108-14 pubmed
    ..Collectively, our study has identified Erbin as a novel suppressor of the Ras signaling by disrupting the Ras-Raf interaction. ..
  45. Karbowniczek M, Cash T, Cheung M, Robertson G, Astrinidis A, Henske E. Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. J Biol Chem. 2004;279:29930-7 pubmed
    ..Taken together these data demonstrate that inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin. ..
  46. Park S, Park C, Hahm E, Kim K, Kimler B, Lee S, et al. Activation of Raf1 and the ERK pathway in response to l-ascorbic acid in acute myeloid leukemia cells. Cell Signal. 2005;17:111-9 pubmed
  47. Kim H, Kim G, Lim S, Park Y, Kim Y. Reduced expression of Raf-1 kinase inhibitory protein is a significant prognostic marker in patients with gallbladder carcinoma. Hum Pathol. 2010;41:1609-16 pubmed publisher
    ..020). Our results suggest that reduction in Raf-1 kinase inhibitory protein expression in gallbladder carcinoma contributes to invasion and metastasis and is a significant prognostic marker in patients with gallbladder carcinoma. ..
  48. Baradaran Ghavami S, Chaleshi V, Derakhshani S, Aimzadeh P, Asadzadeh Aghdaie H, Zali M. Association between TNF-? rs1799964 and RAF1 rs1051208 MicroRNA binding site SNP and gastric cancer susceptibility in an Iranian population. Gastroenterol Hepatol Bed Bench. 2017;10:214-219 pubmed
    ..The aim of this study was to find the relationship between rs1799964 in TNF-? gene as well as rs1051208 of RAF1 gene SNPs on GC in an Iranian population...
  49. Mollapour M, Tsutsumi S, Truman A, Xu W, Vaughan C, Beebe K, et al. Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity. Mol Cell. 2011;41:672-81 pubmed publisher
    ..Overexpression of Aha1 stimulates the ATPase activity, restores cochaperone interactions, and compensates for the functional defects of these Hsp90 mutants. ..
  50. Yaoita M, Niihori T, Mizuno S, Okamoto N, Hayashi S, Watanabe A, et al. Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. Hum Genet. 2016;135:209-22 pubmed publisher
  51. Cipriano R, Miskimen K, Bryson B, Foy C, Bartel C, Jackson M. Conserved oncogenic behavior of the FAM83 family regulates MAPK signaling in human cancer. Mol Cancer Res. 2014;12:1156-65 pubmed publisher
    ..family with sequence similarity 83, member B) was recently identified as a novel oncogene involved in activating CRAF/MAPK signaling and driving epithelial cell transformation...
  52. Kamemura N, Murakami S, Komatsu H, Sawanoi M, Miyamoto K, Ishidoh K, et al. Type II cGMP-dependent protein kinase negatively regulates fibroblast growth factor signaling by phosphorylating Raf-1 at serine 43 in rat chondrosarcoma cells. Biochem Biophys Res Commun. 2017;483:82-87 pubmed publisher
    ..Finally, we found that a phospho-mimic mutant, Raf-1 S43D, suppressed FGF2-induced MAPK pathway. These results suggest that PKGII counters FGF-induced MEK/ERK activation through the phosphorylation of Raf-1 at Ser-43 in chondrocytes. ..
  53. Thorson J, Yu L, Hsu A, Shih N, Graves P, Tanner J, et al. 14-3-3 proteins are required for maintenance of Raf-1 phosphorylation and kinase activity. Mol Cell Biol. 1998;18:5229-38 pubmed
    ..This supports a paradigm in which the effects of phosphorylation on serine as well as tyrosine residues are mediated by inducible protein-protein interactions. ..
  54. Maki M, Matsukawa N, Yuasa H, Otsuka Y, Yamamoto T, Akatsu H, et al. Decreased expression of hippocampal cholinergic neurostimulating peptide precursor protein mRNA in the hippocampus in Alzheimer disease. J Neuropathol Exp Neurol. 2002;61:176-85 pubmed
  55. Wang M, Xu S, Lei H, Wang C, Xiao Z, Jia S, et al. Design, synthesis and antitumor activity of Novel Sorafenib derivatives bearing pyrazole scaffold. Bioorg Med Chem. 2017;25:5754-5763 pubmed publisher
    ..cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases...
  56. Takezawa K, Okamoto I, Yonesaka K, Hatashita E, Yamada Y, Fukuoka M, et al. Sorafenib inhibits non-small cell lung cancer cell growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells. Cancer Res. 2009;69:6515-21 pubmed publisher
    ..Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS. ..
  57. Yoshiki S, Matsunaga Udagawa R, Aoki K, Kamioka Y, Kiyokawa E, Matsuda M. Ras and calcium signaling pathways converge at Raf1 via the Shoc2 scaffold protein. Mol Biol Cell. 2010;21:1088-96 pubmed publisher
    ..These observations indicated that the Shoc2 scaffold protein modulates Ras-dependent Raf1 activation in a Ca(2+)- and calmodulin-dependent manner. ..
  58. Motta M, Chillemi G, Fodale V, Cecchetti S, Coppola S, Stipo S, et al. SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling. Hum Mol Genet. 2016;25:3824-3835 pubmed publisher
  59. Pandit B, Sarkozy A, Pennacchio L, Carta C, Oishi K, Martinelli S, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39:1007-12 pubmed
    ..Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy...
  60. Yan F, Zhang M, Meng Y, Li H, Yu L, Fu X, et al. Erythropoietin improves hypoxic-ischemic encephalopathy in neonatal rats after short-term anoxia by enhancing angiogenesis. Brain Res. 2016;1651:104-113 pubmed publisher
    ..Our data indicate that rhEPO can enhance angiogenesis, reduce white matter damage, and promote cognitive recovery through VEGF/VEGFR2 signaling pathway in anoxia rats. ..
  61. Albano G, Bonanno A, Moscato M, Anzalone G, Di Sano C, Riccobono L, et al. Crosstalk between mAChRM3 and ?2AR, via acetylcholine PI3/PKC/PBEP1/Raf-1 MEK1/2/ERK1/2 pathway activation, in human bronchial epithelial cells after long-term cigarette smoke exposure. Life Sci. 2018;192:99-109 pubmed publisher
    ..The use of anticholinergic drugs and long-acting ?2-agonists, alone or in combination may be dampen these inflammatory mechanisms when used in combination in some epithelial cell types. ..
  62. Andersen S, Keijzers G, Rampakakis E, Engels K, Luhn P, El Shemerly M, et al. 14-3-3 checkpoint regulatory proteins interact specifically with DNA repair protein human exonuclease 1 (hEXO1) via a semi-conserved motif. DNA Repair (Amst). 2012;11:267-77 pubmed publisher
    ..Altogether, these results suggest that association may be related to regulation of hEXO1 availability during the DNA damage response to plausibly prevent extensive DNA resection at the damage site, as supported by recent studies. ..
  63. Kubota Y, O Grady P, Saito H, Takekawa M. Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation. Nat Cell Biol. 2011;13:282-91 pubmed publisher
    ..Thus, oncogenic Ras efficiently activates the ERK pathway both by activating Raf and by inhibiting MEK SUMOylation, thereby inducing carcinogenesis. ..
  64. Koyama S, Williams L, Kikuchi A. Characterization of the interaction of Raf-1 with ras p21 or 14-3-3 protein in intact cells. FEBS Lett. 1995;368:321-5 pubmed
    ..While Raf(1-135) did not interact with 14-3-3 protein, Raf(136-322) did. These results clearly indicate that Raf-1 simultaneously interacts with both ras p21 and 14-3-3 protein through the distinct binding domains in intact cells. ..
  65. Ziogas A, Moelling K, Radziwill G. CNK1 is a scaffold protein that regulates Src-mediated Raf-1 activation. J Biol Chem. 2005;280:24205-11 pubmed
    ..Down-regulation of endogenously expressed CNK1 by small inhibitory RNA interferes with Src-dependent activation of ERK. Thus, CNK1 allows cross-talk between Src and Raf-1 and is essential for the full activation of Raf-1. ..
  66. Haling J, Sudhamsu J, Yen I, Sideris S, Sandoval W, Phung W, et al. Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling. Cancer Cell. 2014;26:402-413 pubmed publisher
    ..Taken together, these findings reveal a regulatory role for BRAF in the MAPK pathway independent of its kinase activity but dependent on interaction with MEK. ..
  67. Lito P, Saborowski A, Yue J, SOLOMON M, Joseph E, Gadal S, et al. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell. 2014;25:697-710 pubmed publisher
    ..To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition...
  68. Lorenz K, Lohse M, Quitterer U. Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature. 2003;426:574-9 pubmed
    ..A physiological role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains beta-adrenergic signalling and contractile activity. ..
  69. Takahashi H, Ibe M, Honma M, Ishida Yamamoto A, Hashimoto Y, Iizuka H. 1,25-dihydroxyvitamin D(3) increases human cystatin A expression by inhibiting the Raf-1/MEK1/ERK signaling pathway of keratinocytes. Arch Dermatol Res. 2003;295:80-7 pubmed
  70. Luttrell L, Roudabush F, Choy E, Miller W, Field M, Pierce K, et al. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci U S A. 2001;98:2449-54 pubmed
    ..of multiprotein complexes containing AT1aR, beta-arrestin-2, and the component kinases of the ERK cascade, cRaf-1, MEK1, and ERK2...
  71. Movilla N, Crespo P, Bustelo X. Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins. Oncogene. 1999;18:5860-9 pubmed
    ..From these results, we conclude that TC21 promotes Ras-like responses in diverse cell types due to the use of overlapping, if not identical, signaling elements of the Ras oncogenic pathway. ..
  72. Sakatsume M, Stancato L, David M, Silvennoinen O, Saharinen P, Pierce J, et al. Interferon gamma activation of Raf-1 is Jak1-dependent and p21ras-independent. J Biol Chem. 1998;273:3021-6 pubmed
    ..These observations suggest that a kinase-active Jak1 is required for IFNgamma activation of Raf-1 that is p21(ras)-independent. ..
  73. Matissek K, Onozato M, Sun S, Zheng Z, Schultz A, Lee J, et al. Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor-Positive Breast Cancer. Cancer Discov. 2018;8:336-353 pubmed publisher
    ..i>Cancer Discov; 8(3); 336-53. ©2017 AACR.See related commentary by Natrajan et al., p. 272See related article by Liu et al., p. 354This article is highlighted in the In This Issue feature, p. 253. ..