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Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma.
Imielinski M, Greulich H, Kaplan B, Araujo L, Amann J, Horn L, Schiller J, Villalona-Calero MA, Meyerson M, Carbone DP
(2014) J Clin Invest 124: 1582-6
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Aged, Amino Acid Substitution, Antineoplastic Agents, Cell Transformation, Neoplastic, DNA, Neoplasm, Female, Humans, Lung Neoplasms, Molecular Targeted Therapy, Mutation, Missense, Niacinamide, Oncogenes, Phenylurea Compounds, Proto-Oncogene Proteins A-raf, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-raf, Sorafenib
Show Abstract · Added June 26, 2014
Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.
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19 MeSH Terms
Small G proteins Rac1 and Ras regulate serine/threonine protein phosphatase 5 (PP5)·extracellular signal-regulated kinase (ERK) complexes involved in the feedback regulation of Raf1.
Mazalouskas MD, Godoy-Ruiz R, Weber DJ, Zimmer DB, Honkanen RE, Wadzinski BE
(2014) J Biol Chem 289: 4219-32
MeSH Terms: Amino Acid Substitution, Animals, Cattle, Cell Line, Extracellular Signal-Regulated MAP Kinases, Glycoproteins, Humans, Multienzyme Complexes, Mutation, Missense, Phosphorylation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-raf, Proto-Oncogene Proteins p21(ras), Rats, rac1 GTP-Binding Protein, ras Proteins
Show Abstract · Added March 26, 2014
Serine/threonine protein phosphatase 5 (PP5, PPP5C) is known to interact with the chaperonin heat shock protein 90 (HSP90) and is involved in the regulation of multiple cellular signaling cascades that control diverse cellular processes, such as cell growth, differentiation, proliferation, motility, and apoptosis. Here, we identify PP5 in stable complexes with extracellular signal-regulated kinases (ERKs). Studies using mutant proteins reveal that the formation of PP5·ERK1 and PP5·ERK2 complexes partially depends on HSP90 binding to PP5 but does not require PP5 or ERK1/2 activity. However, PP5 and ERK activity regulates the phosphorylation state of Raf1 kinase, an upstream activator of ERK signaling. Whereas expression of constitutively active Rac1 promotes the assembly of PP5·ERK1/2 complexes, acute activation of ERK1/2 fails to influence the phosphatase-kinase interaction. Introduction of oncogenic HRas (HRas(V12)) has no effect on PP5-ERK1 binding but selectively decreases the interaction of PP5 with ERK2, in a manner that is independent of PP5 and MAPK/ERK kinase (MEK) activity, yet paradoxically requires ERK2 activity. Additional studies conducted with oncogenic variants of KRas4B reveal that KRas(L61), but not KRas(V12), also decreases the PP5-ERK2 interaction. The expression of wild type HRas or KRas proteins fails to reduce PP5-ERK2 binding, indicating that the effect is specific to HRas(V12) and KRas(L61) gain-of-function mutations. These findings reveal a novel, differential responsiveness of PP5-ERK1 and PP5-ERK2 interactions to select oncogenic Ras variants and also support a role for PP5·ERK complexes in regulating the feedback phosphorylation of PP5-associated Raf1.
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16 MeSH Terms
FAM83B mediates EGFR- and RAS-driven oncogenic transformation.
Cipriano R, Graham J, Miskimen KL, Bryson BL, Bruntz RC, Scott SA, Brown HA, Stark GR, Jackson MW
(2012) J Clin Invest 122: 3197-210
MeSH Terms: Amino Acid Sequence, Animals, Antineoplastic Agents, Base Sequence, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Epithelial Cells, ErbB Receptors, Erlotinib Hydrochloride, Gene Expression, Gene Knockdown Techniques, Humans, Mammary Glands, Human, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Sequence Data, Neoplasm Proteins, Neoplasm Transplantation, Neoplasms, Oligonucleotide Array Sequence Analysis, Protein Structure, Tertiary, Proto-Oncogene Proteins c-raf, Quinazolines, RNA Interference, Signal Transduction, TOR Serine-Threonine Kinases, Transcriptome, ras Proteins
Show Abstract · Added March 21, 2013
Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using validation-based insertional mutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), based on its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells (HMECs). We found that FAM83B coprecipitated with a downstream effector of RAS, CRAF. Binding of FAM83B with CRAF disrupted CRAF/14-3-3 interactions and increased CRAF membrane localization, resulting in elevated MAPK and mammalian target of rapamycin (mTOR) signaling. Ablation of FAM83B inhibited the proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs, implicating FAM83B as a key intermediary in EGFR/RAS/MAPK signaling. Analysis of human tumor specimens revealed that FAM83B expression was significantly elevated in cancer and was associated with specific cancer subtypes, increased tumor grade, and decreased overall survival. Cumulatively, these results suggest that FAM83B is an oncogene and potentially represents a new target for therapeutic intervention.
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31 MeSH Terms
The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.
Coffa S, Breitman M, Hanson SM, Callaway K, Kook S, Dalby KN, Gurevich VV
(2011) PLoS One 6: e28723
MeSH Terms: Animals, Arrestin, Arrestins, COS Cells, Cattle, Chlorocebus aethiops, Embryo, Mammalian, Enzyme Activation, Fibroblasts, HEK293 Cells, Humans, Ligands, MAP Kinase Kinase 1, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mutant Proteins, Phosphorylation, Protein Binding, Protein Conformation, Proto-Oncogene Proteins c-raf, Receptors, Adrenergic, beta-2, Structure-Activity Relationship, beta-Arrestins
Show Abstract · Added December 10, 2013
Arrestins are multifunctional signaling adaptors originally discovered as proteins that "arrest" G protein activation by G protein-coupled receptors (GPCRs). Recently GPCR complexes with arrestins have been proposed to activate G protein-independent signaling pathways. In particular, arrestin-dependent activation of extracellular signal-regulated kinase 1/2 (ERK1/2) has been demonstrated. Here we have performed in vitro binding assays with pure proteins to demonstrate for the first time that ERK2 directly binds free arrestin-2 and -3, as well as receptor-associated arrestins-1, -2, and -3. In addition, we showed that in COS-7 cells arrestin-2 and -3 association with β(2)-adrenergic receptor (β2AR) significantly enhanced ERK2 binding, but showed little effect on arrestin interactions with the upstream kinases c-Raf1 and MEK1. Arrestins exist in three conformational states: free, receptor-bound, and microtubule-associated. Using conformationally biased arrestin mutants we found that ERK2 preferentially binds two of these: the "constitutively inactive" arrestin-Δ7 mimicking microtubule-bound state and arrestin-3A, a mimic of the receptor-bound conformation. Both rescue arrestin-mediated ERK1/2/activation in arrestin-2/3 double knockout fibroblasts. We also found that arrestin-2-c-Raf1 interaction is enhanced by receptor binding, whereas arrestin-3-c-Raf1 interaction is not.
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25 MeSH Terms
Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells.
Taylor JR, Lehmann BD, Chappell WH, Abrams SL, Steelman LS, McCubrey JA
(2011) Oncotarget 2: 610-26
MeSH Terms: Antibiotics, Antineoplastic, Antineoplastic Agents, Hormonal, Breast Neoplasms, Cell Line, Tumor, Cellular Senescence, Dose-Response Relationship, Drug, Doxorubicin, Drug Resistance, Neoplasm, Female, Humans, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-raf, Signal Transduction, Tamoxifen, Time Factors, Transfection
Show Abstract · Added January 20, 2015
Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.
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16 MeSH Terms
A single mutation in arrestin-2 prevents ERK1/2 activation by reducing c-Raf1 binding.
Coffa S, Breitman M, Spiller BW, Gurevich VV
(2011) Biochemistry 50: 6951-8
MeSH Terms: Arrestins, Blotting, Western, Cell Line, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Humans, Immunoprecipitation, Models, Molecular, Mutagenesis, Site-Directed, Protein Binding, Proto-Oncogene Proteins c-raf
Show Abstract · Added December 10, 2013
Arrestins regulate the signaling and trafficking of G protein-coupled receptors (GPCRs). GPCR complexes with both nonvisual arrestins channel signaling to G protein-independent pathways, one of which is the activation of extracellular signal regulated kinase 1/2 (ERK1/2). Here we used alanine-scanning mutagenesis of residues on the nonreceptor-binding surface conserved between arrestin-2 and arrestin-3. We show that an Arg307Ala mutation significantly reduced arrestin-2 binding to c-Raf1, whereas the binding of the mutant to active phosphorylated receptor and downstream kinases MEK1 and ERK2 was not affected. In contrast to wild-type arrestin-2, the Arg307Ala mutant failed to rescue arrestin-dependent ERK1/2 activation via β2-adrenergic receptor in arrestin-2/3 double knockout mouse embryonic fibroblasts. Thus, Arg307 plays a specific role in arrestin-2 binding to c-Raf1 and is indispensable in the productive scaffolding of c-Raf1-MEK1-ERK1/2 signaling cascade. Arg307Ala mutation specifically eliminates arrestin-2 signaling through ERK, which makes arrestin-2-Arg307Ala the first signaling-biased arrestin mutant constructed. In the crystal structure the side chain of homologous arrestin-3 residue Lys308 points in a different direction. Alanine substitution of Lys308 does not significantly affect c-Raf1 binding to arrestin-3 and its ability to promote ERK1/2 activation, suggesting that the two nonvisual arrestins perform the same function via distinct molecular mechanisms.
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11 MeSH Terms
TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NF-kappaB.
Edelblum KL, Goettel JA, Koyama T, McElroy SJ, Yan F, Polk DB
(2008) J Biol Chem 283: 29485-94
MeSH Terms: Animals, Apoptosis, Cell Survival, Cells, Cultured, Colon, Epithelial Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, NF-kappa B, Phosphorylation, Proto-Oncogene Proteins c-raf, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction
Show Abstract · Added March 20, 2014
Tumor necrosis factor (TNF) is a therapeutic target in the treatment of inflammatory bowel disease; however, the exact role of TNF signaling in the colon epithelium remains unclear. We demonstrate that TNF activation of TNF receptor (R)1 stimulates both pro- and anti-apoptotic signaling pathways in the colon epithelium; however, TNFR1 protects against colon epithelial cell apoptosis following TNF exposure. To investigate anti-apoptotic signaling pathways downstream of TNFR1, we generated an intestinal epithelium-specific Raf knock-out mouse and identified Raf kinase as a key regulator of colon epithelial cell survival in response to TNF. Surprisingly, Raf promotes NF-kappaB p65 phosphorylation, independent of MEK signaling, to support cell survival. Taken together, these data demonstrate a novel pathway in which Raf promotes colon epithelial cell survival through NF-kappaB downstream of TNFR1 activation. Thus, further understanding of colon epithelial cell-specific TNFR signaling may result in the identification of new targets for inflammatory bowel disease treatment and define novel mediators of colitis-associated cancer.
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15 MeSH Terms
Constitutive activation of Raf-1 induces glioma formation in mice.
Lyustikman Y, Momota H, Pao W, Holland EC
(2008) Neoplasia 10: 501-10
MeSH Terms: Animals, Animals, Newborn, Blotting, Western, Brain, Brain Neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Genes, ras, Glioblastoma, Humans, Immunoenzyme Techniques, Mice, Mice, Knockout, Mutation, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-raf
Show Abstract · Added March 24, 2014
In human glioblastoma multiforme (GBM), RAS activity is upregulated in the majority of the tumors. Furthermore, the levels of phospho-mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK), a downstream effector of RAS, are also increased. In mice, activated KRas cooperates with the loss of INK4a-ARF locus or with activated Akt to induce gliomas, confirming an important role for this pathway in glioma biology. However, to correctly target therapies against the RAS signaling pathway, it is necessary to identify the effectors that contribute to RAS-mediated gliomagenesis. In this study, we investigated the contribution of RAF signaling in glioma oncogenesis. We find that the levels of RAF-1 and BRAF proteins and RAF kinase activity are increased in human GBM samples. We confirm the importance of this finding by demonstrating a causal role for a constitutively active Raf-1 mutant in glioma formation in mice. Specifically, we find that activated Raf-1 cooperates with Arf loss or Akt activation to generate gliomas similar to activated KRas under the same conditions. Our study suggests that the oncogenic effect of KRas in glioma formation may be transduced at least in part through Raf signaling and that therapeutic targeting of this pathway may be beneficial in glioma treatment.
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16 MeSH Terms
Rafs constitute a nodal point in the regulation of embryonic endothelial progenitor cell growth and differentiation.
Bidzhekov K, Hautmann M, Semisch M, Weber C, Engelmann B, Hatzopoulos AK
(2007) J Cell Mol Med 11: 1395-407
MeSH Terms: Animals, Cell Differentiation, Cell Proliferation, Cell Separation, Cloning, Molecular, Embryo, Mammalian, Endothelial Cells, Enzyme Activation, Estrogens, Genetic Engineering, Mice, Models, Biological, Phosphorylation, Protein Structure, Tertiary, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-raf, RNA Interference, Receptors, Estrogen, Recombinant Fusion Proteins, Stem Cells
Show Abstract · Added November 18, 2010
Mouse embryonic endothelial progenitor cells (eEPCs) acquire a mature phenotype after treatment with cyclic adenosine monophosphate (cAMP), suggesting an involvement of Raf serine/threonine kinases in the differentiation process. To test this idea, we investigated the role of B-Raf and C-Raf in proliferation and differentiation of eEPCs by expressing fusion proteins consisting of the kinase domains from Raf molecules and the hormone binding site of the estrogen receptor (ER), or its variant, the tamoxifen receptor. Our findings show that both B- and C-Raf kinase domains, when lacking adjacent regulatory parts, are equally effective in inducing eEPC differentiation. In contrast, the C-Raf kinase domain is a more potent stimulator of eEPC proliferation than B-Raf. In a complimentary approach, we used siRNA silencing to knockdown endogenously expressed B-Raf and C-Raf in eEPCs. In this experimental setting, we found that eEPCs lacking B-Raf failed to differentiate, whereas loss-of C-Raf function primarily slowed cell growth without impairing cAMP-induced differentiation. These findings were further corroborated in B-Raf null eEPCs, isolated from the corresponding knockout embryos, which failed to differentiate in vitro. Thus, gain- and loss-of-function experiments point to distinct roles of B-Raf and C-Raf in regulating growth and differentiation of endothelial progenitor cells, which may harbour therapeutic implications.
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20 MeSH Terms
Phosphorylation of Rad55 on serines 2, 8, and 14 is required for efficient homologous recombination in the recovery of stalled replication forks.
Herzberg K, Bashkirov VI, Rolfsmeier M, Haghnazari E, McDonald WH, Anderson S, Bashkirova EV, Yates JR, Heyer WD
(2006) Mol Cell Biol 26: 8396-409
MeSH Terms: Adenosine Triphosphatases, Amino Acid Sequence, Cell Cycle Proteins, Checkpoint Kinase 2, DNA Damage, DNA Repair, DNA Repair Enzymes, DNA Replication, DNA, Fungal, DNA-Binding Proteins, Gene Expression Regulation, Fungal, Genome, Mass Spectrometry, Models, Genetic, Molecular Sequence Data, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-raf, Rad52 DNA Repair and Recombination Protein, Recombination, Genetic, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Serine
Show Abstract · Added March 20, 2014
DNA damage checkpoints coordinate the cellular response to genotoxic stress and arrest the cell cycle in response to DNA damage and replication fork stalling. Homologous recombination is a ubiquitous pathway for the repair of DNA double-stranded breaks and other checkpoint-inducing lesions. Moreover, homologous recombination is involved in postreplicative tolerance of DNA damage and the recovery of DNA replication after replication fork stalling. Here, we show that the phosphorylation on serines 2, 8, and 14 (S2,8,14) of the Rad55 protein is specifically required for survival as well as for normal growth under genome-wide genotoxic stress. Rad55 is a Rad51 paralog in Saccharomyces cerevisiae and functions in the assembly of the Rad51 filament, a central intermediate in recombinational DNA repair. Phosphorylation-defective rad55-S2,8,14A mutants display a very slow traversal of S phase under DNA-damaging conditions, which is likely due to the slower recovery of stalled replication forks or the slower repair of replication-associated DNA damage. These results suggest that Rad55-S2,8,14 phosphorylation activates recombinational repair, allowing for faster recovery after genotoxic stress.
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23 MeSH Terms