Second nature: Biological functions of the Raf-1 “kinase”

Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, The University of Vienna, Vienna Biocenter, Dr. Bohr Gasse 9, 1030 Vienna, Austria.
FEBS Letters (Impact Factor: 3.17). 07/2005; 579(15):3271-7. DOI: 10.1016/j.febslet.2005.03.024
Source: PubMed


More than 20 years ago, Raf was discovered as a cellular oncogene transduced by transforming retroviruses. Since then, the three Raf isoforms have been intensively studied, mainly as the kinases linking Ras to the MEK/ERK signaling module. As this pathway is activated in human cancer, the Raf kinases are considered promising therapeutic targets, and we have learned a lot about their regulation, targets, and functions. 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.

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Available from: Manuela Baccarini,
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    • "It has been evidenced that HIV-1 can mediate the activation of Raf-1 kinase through the DC-SIGN signalosome, thus modulating the cytokine responses to HIV-1 [35]. Raf-1 activation occurs through an interaction with the active form of Ras-GTPase [36]. Also, Raf-1 activation by DC-SIGN can induce phosphorylation of NF-êB to shape the adaptive immunity [35]. "
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    ABSTRACT: HIV-1 replication is a tightly controlled mechanism which demands the interplay of host as well as viral factors. Both gp120 (envelope glycoprotein) and Nef (regulatory protein) have been correlated with the development of AIDS disease in independent studies. In this context, the ability of HIV-1 to utilize immature dentritic cells for transfer of virus is pivotal for early pathogenesis. The presence of C-type lectins on dendritic cells (DCs) like DC-SIGN, are crucial in inducing antiviral immunity to HIV-1. Both gp120 and Nef induce the release of cytokines leading to multiple effects of viral pathogenesis. Our study elucidated for the first time the cross-talk of the signaling mechanism of these two viral proteins in immature monocyte derived dentritic cells (immDCs). Further, gp120 was found to downregulate the IL-6 release by Nef, depending on the interaction with DC-SIGN. A cascade of signaling followed thereafter, including the activation of SOCS-3, to mediate the diminishing effect of gp120. Our results also revealed that the anti-apoptotic signals emanated from Nef was put to halt by gp120 through inhibition of Nef induced STAT3. Thus our results implicate that the signaling generated by gp120 and Nef, undergoes a switch-over mechanism that significantly contributes to the pathogenesis of HIV-1 and widens our view towards the approach on battling the viral infection.
    PLoS ONE 10/2013; 8(3):e59073. DOI:10.1371/journal.pone.0059073 · 3.23 Impact Factor
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    • "The RAS-RAF-MEK-ERK signaling pathway is key for a variety of cellular functions including controlling cell proliferation and survival (Baccarini, 2005; Wellbrock et al., 2004). Dysregulation of this pathway is also important in cancer with most tumors exhibiting mutations in RAS and/or RAF (Brose et al., 2002). "
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    ABSTRACT: Although RAF kinases are critical for controlling cell growth, their mechanism of activation is incompletely understood. Recently, dimerization was shown to be important for activation. Here we show that the dimer is functionally asymmetric with one kinase functioning as an activator to stimulate activity of the partner, receiver kinase. The activator kinase did not require kinase activity but did require N-terminal phosphorylation that functioned allosterically to induce cis-autophosphorylation of the receiver kinase. Based on modeling of the hydrophobic spine assembly, we also engineered a constitutively active mutant that was independent of Ras, dimerization, and activation-loop phosphorylation. As N-terminal phosphorylation of BRAF is constitutive, BRAF initially functions to activate CRAF. N-terminal phosphorylation of CRAF was dependent on MEK, suggesting a feedback mechanism and explaining a key difference between BRAF and CRAF. Our work illuminates distinct steps in RAF activation that function to assemble the active conformation of the RAF kinase.
    Cell 08/2013; 154(5):1036-46. DOI:10.1016/j.cell.2013.07.046 · 32.24 Impact Factor
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    • "Cyclin D, CDK4, Wee1) known to regulate cancer cell proliferation and survival (Fig. 3A), LD053 dissociated cdc37 from Hsp90 (Fig. 2A) leading to proteosomal degradation of Akt and c-Raf (Fig. 2E and F). Akt and c-Raf mediate activation of two major oncogenic signaling pathways that regulate a large variety of cellular functions including proliferation, survival, apoptosis, and migration (Fig. 4A) [37] [38] [39] [40]. Accordingly, LD053-caused destabilization of Akt/c-Raf would result in inhibition of Akt/c-Raf-mediated signaling frequently elevated in various human cancers [37]. "
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    ABSTRACT: Heat shock protein 90 (Hsp90) is a molecular chaperone engaging multiple cellular signaling by stabilizing oncoproteins (e.g., Akt and c-Raf) in tumor cells. Whereas Hsp90 inhibitors such as 17-AAG exert promising antitumor effects in clinical trials, current efforts focus on developing agents targeting Hsp90 with improved efficacy and lower toxicity. Using a fluorescence polarization assay, we screened over a hundred of synthetic small molecules and identified a resorcinol derivative LD053 that bound the Hsp90 ATP-binding pocket. The binding of LD053 to Hsp90 dissociated the co-chaperone protein cdc37 from Hsp90, resulting in destabilization of Akt and c-Raf and subsequent inhibition of PI3K/Akt and c-Raf/Mek/Erk signaling in BGC823 gastric cancer cells. As a consequence, LD053 decreased cancer cell viability and induced apoptosis evidenced by increased subG0/G1 cell population and increased cleavage of caspase 3 and PARP. Interestingly, normal human cells appeared insensitive to LD053 treatments. Consistent with its in vitro anticancer activities, LD053 significantly inhibited growth of BGC823 xenografts in nude mice without apparent body weight loss. These results thus demonstrate that LD053 is a novel Hsp90 inhibitor and has potential to be used to treat gastric cancer.
    Biochemical pharmacology 02/2013; 85(9). DOI:10.1016/j.bcp.2013.02.003 · 5.01 Impact Factor
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