The RAF proteins take centre stage. Nat. Rev

Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 12/2004; 5(11):875-85. DOI: 10.1038/nrm1498
Source: PubMed

ABSTRACT Since their discovery over 20 years ago, the RAF proteins have been intensely studied. For most of that time, the focus of the field has been the C-RAF isoform and its role as an effector of the RAS proteins. However, a report that implicates B-RAF in human cancer has highlighted the importance of all members of this protein kinase family and recent studies have uncovered intriguing new data relating to their complex regulation and biological functions.

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Available from: Maria Karasarides, Sep 26, 2015
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    • "A major event in the neoplastic transformation of thyroid follicular cells is the constitutive activation of oncogenes: BRAF, RAS, or RET/PTC, a chromosomal rearrangement leading to the fusion between the 3 0 end of the RET receptor tyrosine kinase gene and a 5 0 fragment of various unrelated genes (Soares et al., 2004). These genetic alterations are associated with activation of the MEKeERK and/or the PI3K pathways, resulting in alteration of a variety of transcription factors that regulate cellular proliferation, differentiation and apoptosis Q3 (Ji et al., 2007; Nikiforov, 2002; Sobrinho-Sim~ oes et al., 2008; Wellbrock et al., 2004). "
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    ABSTRACT: Thyroid cancer (TC) is frequently associated with BRAF or RAS oncogenic mutations and RET/PTC rearrangements, with aberrant RAF-MEK-ERK and/or PI3K pathway activation. BRAF underlies ERK activation in most TC cells, but not in TPC-1 cells with RET/PTC1 rearrangement. Here, we show that depletion of RAF-1, a RAF family member with a poorly defined role in TC, decreases proliferation and increases apoptosis in TPC-1 cells and, less significantly, in cells harboring a BRAF(V600E) or HRAS(G13R) mutations, but without affecting ERK activation. We further demonstrate that constitutive activation of ERKs in TPC-1 cells is not caused by mutations in 50 oncogenes and tumor suppressors prone to activate the ERK pathway, or affected by inhibition of BRAF, MEK1/2 or PI3K. Our data indicate that RAF-1 is important for the survival of TPC-1 cells independently of the classical MEK1/2-ERK activation, offering new perspectives on RET/PTC signaling and for the therapy of thyroid cancers. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 08/2015; DOI:10.1016/j.mce.2015.08.006 · 4.41 Impact Factor
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    • "By contrast, LS mutants behaved as loss-of-function mutations of SHP2, impairing ERK activation [10] [11] [12]. Within the heart, ERK1/2 are activated at the plasma membrane by Raf-1, followed by activation of small G protein Ras [13]. Harris et al. showed that dominant negative Raf-1 inhibited ERK1/2 activation in transgenic mice, which were resistant to hypertrophic stress but developed significant cardiomyocyte apoptosis [14]. "
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    ABSTRACT: Mitogen-activated protein kinases (MAPKs) are involved in the regulation of cardiac hypertrophy and myocyte survival. Extracellular signal regulated protein kinase 1 and 2 (ERK1/2) are key components in the MAPKs signaling pathways. Dysfunction of ERK1/2 in congenital heart diseases (Noonan syndrome and LEOPARD syndrome) leads to cardiac hypertrophy. ERK2 contributes 70% of protein content to total ERK1/2 content in myocardium, however, the specific role of ERK2 in regulating cardiac hypertrophy is yet to be further defined. To investigate the specific role of ERK2 played in the cardiomyocytes, we generated and examined mice with cardiomyocyte-specific deletion of the erk2 gene (ERK2cko mice). Following short-term pathological hypertrophic stresses, the mutant mice showed attenuated hypertrophic remodeling characterized by a blunted increase in cross-sectional area of individual myocytes, downregulation of hypertrophic foetal gene markers (ANP and BNP), and less interstitial fibrosis. However, increased cardiomyocyte apoptosis was observed. Upon prolonged stimulation, ERK2cko mice developed deterioration in cardiac function. However, absence of ERK2 did not affect physiological hypertrophy induced by 4 weeks of swimming exercise. These results revealed an essential role for ERK2 in cardiomyocytes in the development of pathological hypertrophic remodeling and resistance to cell death.
    Journal of Molecular and Cellular Cardiology 07/2014; 72(100). DOI:10.1016/j.yjmcc.2014.03.002 · 4.66 Impact Factor
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    • "Ras-Raf-MEK-ERK serine threonine kinase cascade, which is also called ERK/MAP kinase pathway or ‘classical’ MAPK pathway, has been convinced to be important for cell proliferation and survival [2], [3]. It can be hyper-activated in up to 30% of human cancers [4]. "
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    ABSTRACT: A series of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-yl)phenol derivatives (C1-C24) have been synthesized. The B-Raf inhibitory activity and anti-proliferation activity of these compounds have been tested. Compound C6 displayed the most potent biological activity against B-RafV600E (IC50 = 0.15 µM) and WM266.4 human melanoma cell line (GI50 = 1.75 µM), being comparable with the positive control (Vemurafenib and Erlotinib) and more potent than our previous best compounds. The docking simulation was performed to analyze the probable binding models and poses while the QSAR model was built to check the previous work as well as to introduce new directions. This work aimed at seeking more potent inhibitors as well as discussing some previous findings. As a result, the introduction of ortho-hydroxyl group on 4,5-dihydro-1H-pyrazole skeleton did reinforce the anti-tumor activity while enlarging the group on N-1 of pyrazoline was also helpful.
    PLoS ONE 05/2014; 9(5):e95702. DOI:10.1371/journal.pone.0095702 · 3.23 Impact Factor
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