Sigma-Aldrich offers abstracts and full-text articles by [Marta Magariños, María R Aburto, Hortensia Sánchez-Calderón, Carmen Muñoz-Agudo, Ulf R Rapp, Isabel Varela-Nieto].

PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Buy our Recombinant Human A RAF protein. Ab127659 is a protein fragment produced in Baculovirus infected Sf9 cells and has been validated in WB, SDS-PAGE…

The Raf-1 protein kinase is the best-characterized downstream effector of activated Ras. Interaction with Ras leads to Raf-1 activation and results in transduction of cell growth and differentiation signals. The details of Raf-1 activation are unclear, but our characterization of a second Ras-binding site in the cysteine-rich domain (CRD) and the involvement of both Ras-binding sites in effective Raf-1-mediated transformation provides insight into the molecular aspects and consequences of Ras-Raf interactions. The Raf-1 CRD is a member of an emerging family of domains, many of which are found within signal transducing proteins. Several contain binding sites for diacylglycerol (or phorbol esters) and phosphatidylserine and are believed to play a role in membrane translocation and enzyme activation. The CRD from Raf-1 does not bind diacylglycerol but interacts with Ras and phosphatidylserine. To investigate the ligand-binding specificities associated with CRDs, we have determined the solution ...

The Raf-1 protein kinase is the best-characterized downstream effector of activated Ras. Interaction with Ras leads to Raf-1 activation and results in transduction of cell growth and differentiation signals. The details of Raf-1 activation are unclear, but our characterization of a second Ras-binding site in the cysteine-rich domain (CRD) and the involvement of both Ras-binding sites in effective Raf-1-mediated transformation provides insight into the molecular aspects and consequences of Ras-Raf interactions. The Raf-1 CRD is a member of an emerging family of domains, many of which are found within signal transducing proteins. Several contain binding sites for diacylglycerol (or phorbol esters) and phosphatidylserine and are believed to play a role in membrane translocation and enzyme activation. The CRD from Raf-1 does not bind diacylglycerol but interacts with Ras and phosphatidylserine. To investigate the ligand-binding specificities associated with CRDs, we have determined the solution ...

TY - JOUR. T1 - Erbin suppresses the MAP kinase pathway. AU - Huang, Yang Z.. AU - Zang, Mengwei. AU - Xiong, Wen C.. AU - Luo, Zhijun. AU - Mei, Lin. PY - 2003/1/10. Y1 - 2003/1/10. N2 - We present evidence here that Erbin is a negative regulator of the Ras-Raf-Erk signaling pathway. Expression of Erbin decreases transcription of the AChR ε-subunit gene, an event that is mediated by Erk activation. Although it interacts with the ErbB2 C terminus through the PDZ domain, Erbin has no effect on ErbB2 tyrosine phosphorylation or binding to the adaptor proteins Shc and Grb2. In contrast, expression of Erbin greatly impairs activation of Erk, but not Akt, by ligands that activate receptor tyrosine kinases. Moreover, Erbin inhibits the Erk activation by active Ras, while it fails to do so in the presence of active Raf-1. Erbin associates with active Ras, but not inactive Ras nor Raf. Consistently, Erbin interferes with the interaction between Ras and Raf both in vivo and in vitro. Finally, ...

A comprehensive and functional analysis of B-Raf signalling (funded by the Emmy-Noether-Program of the DFG) The serine/threonine kinase B-Raf represents an important oncoprotein, which is mutated in about 8 % of all human cancer, with mutation rates rising up to 90 % in certain tumour entities (Röring & Brummer, 2012). Even in the absence of mutations, B-Raf is often dysregulated due to the mutation and/or over-expression of its activators such as Ras or receptor tyrosine kinases (RTKs). B-Raf is regulated by multiple phosphorylation events provided by upstream activators and by crosstalk with other pathways and feedback loops. Using phospho-proteomics, we are currently working towards a more dynamic and refined model of the B-Raf activation cycle (Fig. 1). B-Raf activity is strongly regulated by homo-dimerisation or by heterodimerisation with other Raf-isoforms or KSR proteins. Recently, we have characterised the importance of dimerisation for wildtype, oncogenic and drug-inhibited B-Raf. For ...

GW5074 is a c-Raf inhibitor. GW5074 has no direct effect on the activities of several apoptosis-associated kinases when assayed in vitro. In contrast to its effect in vitro, treatment of neurons with GW5074 causes c-Raf activation (when measured in vitro in the absence of the drug) and stimulates the Raf-MEK-ERK pathway. GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntingtons disease. GW5074 could have therapeutic value against neurodegenerative pathologies in humans.

RAF activation and inhibition. A promising approach is to target the RAF protein, a crucial intermediary in cell signal transmission. Because of its preponderant role in tumor formation, pharmaceutical companies have invested considerable effort to identify molecules that inhibit RAF enzymatic activity. Although there has been some clinical success, it turns out that on the whole these inhibitors have the unfortunate habit of stimulating the growth of cancer cells instead of reducing it; a paradox that has puzzled an entire community of investigators and clinicians.. IRIC investigators recently discovered new elements to explain this paradox by showing how RAF activation requires three interconnected events involving RAF and RAS and how the drugs currently available unexpectedly stimulate some of those interactions. This new understanding at the molecular level results in being able to propose characteristics that the new generation of RAF inhibitors must possess to constitute effective cancer ...

NRAS and its effector BRAF are frequently mutated in melanoma. Paradoxically, CRAF but not BRAF was shown to be critical for various RAS-driven cancers, raising the question of the role of RAF proteins in NRAS-induced melanoma. Here, using conditional ablation of Raf genes in NRAS-induced mouse melanoma models, we investigate their contribution in tumour progression, from the onset of benign tumours to malignant tumour maintenance. We show that BRAF expression is required for ERK activation and nevi development, demonstrating a critical role in the early stages of NRAS-driven melanoma. After melanoma formation, single Braf or Craf ablation is not sufficient to block tumour growth, showing redundant functions for RAF kinases. Finally, proliferation of resistant cells emerging in the absence of BRAF and CRAF remains dependent on ARAF-mediated ERK activation. These results reveal specific and compensatory functions for BRAF and CRAF and highlight an addiction to RAF signalling in NRAS-driven ...

PROTOCOL SUMMARY:. Phase 1: Patients with non-hematologic malignancies that are recurrent, progressive, or refractory after standard up-front therapy receiving MEK162 will define the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and toxicity profile.. Phase 2: Patients with recurrent or progressive tumors signaling through the ras/raf pathway after standard up-front therapy will be treated in three strata to define the activity of MEK162.. Stratum 1: Pediatric patients with recurrent or progressive low-grade glioma (LGG) characterized by a BRAF truncated fusion (KIAA1549 and similar translocations).. Stratum 2: Pediatric patients with neurofibromatosis type 1 (NF1) and recurrent or progressive LGG.. Stratum 3: Pediatric patients with recurrent or progressive tumors thought to involve the ras/raf/MAP pathway but not included in strata 1 or 2. This includes any LGG not included in strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any tumor ...

Activating mutations of the BRAF gene occurs in approximately 60% of melanomas, most often resulting in a V600E mutant. Other substitutions at this and adjacent residues are known to exist, resulting in constitutive B-raf kinase activity and poor clinical prognosis. B-raf mutations may also play a role in the pathogenesis of a number of other malignancies including colorectal, lung, thyroid and hematopoietic cancers. Due to the importance of this target in cancer progression, several potential therapies targeting B-raf are currently in preclinical and clinical development.. To better understand the role of B-raf in melanoma and other cancers we have established and characterized a panel of wildtype and mutated B-raf melanoma, colorectal, ovary and biliary cancer patient-derived tumor models. For each model, tissue was implanted into immune-deficient mice and once established, each model was confirmed by histologic analysis and linked with donor patient treatment and outcome data. In addition, ...

Another purpose of this study is to measure the concentration of drug in the blood to help understand how much drug gets into the body and how quickly the drug is removed from the body. Another purpose of this study is to determine whether MEK162 turns off the Ras/Raf/MAP pathway as expected by measuring this pathway in blood cells. Finally, in this study, the investigators hope to start finding out whether or not MEK162 causes different types of tumors in children to shrink or stop growing ...

Inhibition of the Raf/MEK/ERK pathway is sufficient to partially restore CD24 mRNA but not protein expression in RasV12 cells. (A-C) RasV12 cells were treated

We report the generation of mice with a LSL conditional knock-in mutation of V600EBraf, whereby the expression of endogenous V600EB-Raf is dependent on delivery of the Cre recombinase and deletion of the LSL cassette. We show that somatic tissues expressing endogenous V600EB-Raf have elevated B-Raf kinase activity, elevated levels of phospho-MEK, phospho-ERK, and cyclin D1 expression, and increased proliferation. In addition, expression of V600EB-Raf in primary MEFs induces morphologic transformation as well as hyperproliferation, the loss of contact inhibition, and a weak ability to grow in an anchorage-independent manner. These results show that at least in some primary mouse cells, V600EB-Raf is able to induce several hallmarks of transformation without evidence for the involvement of a second cooperating oncogene or loss of a key tumor suppressor gene.. Classic studies have previously established a requirement for oncogene cooperation in transformation of primary cells (38). RAS and RAF ...

Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes en …

c-Raf, 0.05 ml. The Raf family of serine/threonine-specific kinases is comprised of three members (A-Raf, B-Raf, and c-Raf) that play a critical role in regulating cell growth and differentiation, and couple growth factor receptor stimulation to nuclear

The Raf/MEK/ERK signaling was the first MAP kinase cascade to be characterized. It is probably one of the most well known signal transduction pathways among biologists because of its implication in a wide variety of cellular functions as diverse -and occasionally contradictory- as cell proliferation …

Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS-RAF-MEK-ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS-RAF-MEK-ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G1 phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational ...

In PC12 cells, Ha-Ras modulates multiple effector proteins that induce neuronal differentiation. To regulate these pathways Ha-Ras must be located at the plasma membrane, a process normally requiring attachment of farnesyl and palmitate lipids to the C terminus. Ext61L, a constitutively activated and palmitoylated Ha-Ras that lacks a farnesyl group, induced neurites with more actin cytoskeletal changes and lamellipodia than were induced by farnesylated Ha-Ras61L. Ext61L-triggered neurite outgrowth was prevented easily by co-expressing inhibitory Rho, Cdc42, or p21-activated kinase but required increased amounts of inhibitory Rac. Compared with Ha-Ras61L, Ext61L caused 2-fold greater Rac GTP binding and phosphatidylinositol 3-kinase activity in membranes, a hyperactivation that explained the numerous lamellipodia and ineffectiveness of Rac(N17). In contrast, Ext61L activated B-Raf kinase and ERK phosphorylation more poorly than Ha-Ras61L. Thus, accentuated differentiation by Ext61L apparently results

c-Raf je MAP kinaza kinaza kinaza (MAP3K) koja deluje niže u signalnom putu od Ras potfamilije za membranu vezanih GTPaza za koje se direktno vezuje. Nakon aktivacije Raf-1 može da fosforiliše i time aktivira proteinske kinaze dualne specifičnosti MEK1 i MEK2, koje zatim, fosforilišu serin/treonin specifične proteinske kinaze ERK1 i ERK2. Aktivirane ERK kinaze su pleiotropni efektori ćelijske fiziologije i imaju važnu ulogu u kontroli izražavanja gena koji učestvuju u ćelijskoj deobi, apoptozi, diferencijaciji, i migraciji.[4] ...

Huber, F., Gronwald, W., Wohlgemuth, S., Herrmann, C., Geyer, M., Wittinghofer, A. and Kalbitzer, Hans Robert (2000) Sequential NMR assignment of the RAS-binding domain of Byr2. Journal of Biomolecular NMR 16 (4), pp. 355-356 ...

TY - JOUR. T1 - Innate signaling by the C-type lectin DC-SIGN dictates immune responses. AU - den Dunnen, J.. AU - Gringhuis, S.I.. AU - Geijtenbeek, T.B.H.. PY - 2009. Y1 - 2009. N2 - Effective immune responses depend on the recognition of pathogens by dendritic cells (DCs) through pattern recognition receptors (PRRs). These receptors induce specific signaling pathways that lead to the induction of immune responses against the pathogens. It is becoming evident that C-type lectins are also important PRRs. In particular, the C-type lectin DC-SIGN has emerged as a key player in the induction of immune responses against numerous pathogens by modulating TLR-induced activation. Recent reports have begun to elucidate the molecular mechanisms underlying these immune responses. Upon pathogen binding, DC-SIGN induces an intracellular signaling pathway with a central role for the serine/threonine kinase Raf-1. For several pathogens that interact with DC-SIGN, including Mycobacterium tuberculosis and ...

BACKGROUND: This study is designed to test the toxicity and pharmacokinetics of different doses of BAY 43-9006 (Sorafenib) in patients with Kaposi s sarcoma (KS). It will also assess, in a preliminary manner, the activity of BAY 43-9006 in this disease and its effect on biological markers. BAY 43-9006 is a potent inhibitor of wild-type and mutant c-Raf kinase isoforms. In addition, this agent also inhibits p38, c-kit, vascular endothelial growth factor receptor 2(VEGFR2), VEGF-R3, and platelet derived growth factor receptor beta (PDGFR-B). There is evidence that several of these receptors, and especially VEGF-R2, VEGF-R3, and PDGF-RB, are important in KS pathogenesis. The principle tumor cells of KS lesions are spindle cells, which are derived from endothelial cells. Spindle cells proliferate in response to VEGF, VEGF-C (a ligand for VEGF-R3), and PDGF, and the stimulation of spindle cells by these factors appears to be an important component in the pathogenesis of KS. There is also evidence ...

RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase kinase kinase (MAP3K) that functions downstream of the Ras subfamily of membrane associated GTPases. C-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases, from the TKL (Tyrosine-kinase-like) group of kinases. The first Raf gene, v-Raf was found in 1983. It was isolated from the murine retrovirus bearing the number 3611. It was soon demonstrated to be capable to transform rodent fibroblasts to cancerous cell lines, so this gene was given the name Virus-induced Rapidly Accelerated Fibrosarcoma (V-RAF). A year later, another transforming gene was found in the avian retrovirus MH2, named v-Mil - that turned out to be highly similar to v-Raf. Researchers were able to demonstrate that these genes encode enzymes that have ...

Description: A polyclonal antibody for detection of Raf-1 phospho Ser259) from Human, Mouse, Rat, Monkey. This Raf-1 phospho Ser259) antibody is for WB, IHC-P, ELISA. It is affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific immunogenand is unconjugated. The antibody is produced in rabbit by using as an immunogen synthesized peptide derived from human Raf-1 around the phosphorylation site of ...

cytoplasm, MAP kinase kinase kinase activity, execution phase of apoptosis, nervous system development, regulation of apoptotic process, regulation of mitotic cell cycle, stress-activated protein kinase signaling cascade

The maternal D-raf serine/threonine kinase acts downstream of Torso (Tor) for specification of cell fates at the embryonic termini. D-raf activity is also required in other signal transduction pathways and consistent with its pleiotropic role, we find accumulation of a 90-kD D-raf protein throughout embryonic development. We also characterize the accumulation of maternal D-raf proteins in 0-2-hr embryos derived from females with germ cells lacking D-raf activity. Accumulation of a 90-kD or truncated mutant D-raf protein is observed for some of these embryos, while others lack the maternal D-raf protein. Then, to determine whether rescue of the Tor pathway is influenced by pools of nonfunctional maternal D-raf, wild-type D-raf mRNA was injected into embryos that inherit maternal stores of inactive 90-kD or truncated D-raf protein. For embryos lacking the maternal D-raf protein, a high level of terminal rescue is obtained. In contrast, rescue is reduced or not observed for embryos that accumulate ...

Sigma-Aldrich offers abstracts and full-text articles by [Qi Zhang, Liang Wei, Hongchuan Yang, Wanqi Yang, Qingyu Yang, Zhuofan Zhang, Kailang Wu, Jianguo Wu].

BACKGROUND AND PURPOSE: Artemisinin and its derivatives exhibit potent immunosuppressive activity. The purpose of the current study was to examine the immunosuppressive activity of artemether directly on T lymphocytes and to explore its potential mode of action. EXPERIMENTAL APPROACH: In vitro, T-cell proliferation was measured using [(3)H]-thymidine incorporation assay in cells stimulated with ConA, alloantigen and anti-CD3 antibody. CFSE-labeled cell division and cell cycle distribution were monitored by flow cytometry ...

Soluble molecules (Cytokines) that are found in BM microenvironment such as IL6, IGF1, VEGF, TNF-α, and SDF-1α trigger RAS and activate two different signalling pathways: 1) RAF/MEK/MAPK inducing proliferation of MM cells and 2) PI3K/AKT which prevents apoptosis induced by both ionizing radiation and drugs (see below). The RAS pathway in turn activates NF-KB and endogenous production of IL6. Cytokines such as IL-6 and IL-21 can trigger a third route, the JAK/STAT cascade, that also prevents apoptosis with overexpression of Bcl-XL and inhibition of CD95 (FAS) induced apoptosis. In addition, TNF triggers other transduction signalling routes such as NF-kB and JNK/Ap-1. VEGF and SDF-1α are important in migration. The migration induced by VEGF is mediated by PI3K, which induces downstream activation of PKC. ...

Purpose: Raf-kinases include three major isoforms. Although the role of B-Raf in melanoma is well established, little is known about C-Raf. We studied effects of C-Raf knockdown in vitro and assessed expression of C-Raf in a large cohort of melanomas and nevi.. Experimental Design: Using specific siRNAs, we knocked down C-Raf expression, and determined the effect on viability, MAP extracellular signal-regulated kinase (ERK)/ERK kinase signaling, and apoptosis in seven melanoma cell lines. We determined the IC50 of the C-Raf inhibitors sorafenib and GW5074, and studied the effects of GW5074 on cell signaling. Using an automated method to measure in situ protein expression, we quantified C-Raf expression in 263 nevi and 523 melanomas.. Results: C-Raf was knocked down in three cell lines with detectable phospho-C-Raf, resulting in decreased viability in two of the three (YULAC and YUROB). This resulted in decreased Bcl-2 expression and phospho-Bad cleavage, without affecting phospho-MEK and ...

Anti-Phospho-Raf-1 (S259) polyclonal antibody (STJ90399) was developed using a synthesized peptide derived from human Raf-1 around the phosphorylation site of S259. This antibody is applicable for use in western blot, immunohistochemistry and ELISA protoc

This antibody is designed, produced, and validated as part of a collaboration between Rockland and the National Cancer Institute (NCI) and is suitable for Cancer, Neuroscience, and Signal Transduction research. RREB1 (also known as RAS-responsive element binding protein 1 and Raf responsive zinc finger protein) is a transcription factor that binds specifically to the distal RAS-responsive element (RRE) of gene promoters. May be involved in Ras/Raf-mediated cell differentiation by enhancing calcitonin expression.

Phosphorylation of the activation loop in RAF kinases has been suggested to be critical for changes in activity. The extent to which the activation segment is phosphorylated, the specific structural consequences, and the in vivo relevance have however remained elusive. In this issue of the The EMBO Journal, Köhler et al (2015) addressed these questions by generating a knock‐in mouse expressing a B‐Raf mutant with a non‐phosphorylatable activation loop. The mutant causes a range of developmental phenotypes; intriguingly, it also impairs the tumorigenic potential of a subset of BRAF mutants, suggesting potential new strategies for RAF inhibition.. See also: M Köhler et al (January 2016) ...

Figure 2: Examples of the probability distribution (a, b, and c) and trace plots (d, e, and f) of reaction rates 2 (which indicates the simultaneous recruitment of Shc and Grb2-SOS complex from the cytosol to the cell membrane by the recruitment of EGFR (a and d)), 16 (which shows the activation of MEK proteins by active Raf (b and e)), and 38 (which refers to the dissociation of active ERK and RSK complex (c and f)) of Model 2 under ...

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Mihaly, A.; Olah, Z.; Krug, M.; Kuhnt, U.; Matthies, H.; Rapp, U. R.; Joo, F.: Transient increase of raf protein kinase-like immunoreactivity in the rat dentate gyrus during long-term potentiation. Neuroscience Letters 116 (1-2), pp. 45 - 50 (1990 ...

Model De Cv Raf Wiring Diagram Online,model de cv raf wiring diagram basics, model de cv raf wiring diagram maker, create model de cv raf wiring diagram,

TY - JOUR. T1 - B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS. AU - ODonovan, Kevin J.. AU - Ma, Kaijie. AU - Guo, Hengchang. AU - Wang, Chen. AU - Sun, Fang. AU - Han, Seung Baek. AU - Kim, Hyukmin. AU - Wong, Jamie K.. AU - Charron, Jean. AU - Zou, Hongyan. AU - Son, Young Jin. AU - He, Zhigang. AU - Zhong, Jian. N1 - Copyright: Copyright 2014 Elsevier B.V., All rights reserved.. PY - 2014/5. Y1 - 2014/5. N2 - Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as ...

Gastric cancer (GC) is a threat to human health with increasing incidence and mortality worldwide. Down-regulation or absence of RAF kinase inhibitor protein (RKIP) was associated with the occurrence, differentiation, invasion, and metastasis of GC. This study aims to investigate the molecular mechanisms and biological functions of RKIP in the GC biology. The fusion expression plasmid pcDNA3.1-RKIP-3xFLAG was transfected into SGC7901 cells, the RKIP fusion proteins were purified with anti-flag M2 magnetic beads, and the RKIP-interacting proteins were identified with tandem mass spectrometry (MS/MS), and were analyzed with bioinformatics tools. Western blot and co-immunoprecipitation were used to confirm the interaction complex. A total of 72 RKIP-interacting proteins were identified by MS/MS. Those proteins play roles in enzyme metabolism, molecular chaperoning, biological oxidation, cytoskeleton organization, signal transduction, and enzymolysis. Three RKIP-interaction protein network diagrams were

Cellular signaling downstream of Ras is highly diversified and may involve many different effector molecules. A potential candidate is AF6 which was originally identified as a fusion to ALL-1 in acute myeloid leukemia. In the present work the interaction between Ras and AF6 is characterized and compared with other effectors. The binding characteristics are quite similar to Raf and RalGEF, i.e. nucleotide dissociation as well as GTPase-activating protein activity are inhibited, whereas the intrinsic GTPase activity of Ras is unperturbed by AF6 binding. Particularly, the dynamics of interaction are similar to Raf and RalGEF with a lifetime of the Ras. AF6 complex in the millisecond range. As probed by 31P NMR spectroscopy one of two major conformational states of Ras is stabilized by the interaction with AF6. Looking at the affinities of AF6 to a number of Ras mutants in the effector region, a specificity profile emerges distinct from that of other effector molecules. This finding may be useful in ...

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy in both men and women, and one of the leading causes of cancer-related deaths worldwide. One frequently mutated pathway involved in oncogenesis in CRC is the RAS/RAF/MAP kinase pathway. Oncogenic activation of KRAS and BRAF occur in 30‒40% and 5‒15% of all CRCs, respectively, and the mutations are mutually exclusive. Even though KRAS and BRAF are known to act in the same pathway, KRAS- and BRAF-mutated CRCs have different clinical and histopathological features. For example, BRAF mutation in CRC is tightly linked to microsatellite instability (MSI) and a CpG island methylator phenotype (CIMP), which is not seen in KRAS-mutated tumours. BRAF-mutated CRCs are also more often found in right-sided tumours. However, the underlying molecular reasons for these differences have not yet been defined.. The overall aim of this thesis was to investigate molecular differences between KRAS- and BRAF-mutated CRCs to understand how KRAS ...

Over the past two decades, there have been many attempts to isolate and characterize pharmacological inhibitors targeting Ras-dependent signaling pathways. The small GTPase Ras normally transmits signals downstream of diverse inputs and is a critical signaling node for many cellular activities. Aberrant Ras activity leads to the deregulation of numerous cellular processes including proliferation, survival, cell adhesion and migration, that in turn can contribute to cellular transformation, invasion and metastasis [1], and Ras is mutationally activated in ~30% of cancers [2]. Among the downstream effectors of Ras, the most well-characterized is the Ras-Raf-MAPK signaling pathway, in which Ras interaction with the serine/threonine kinase Raf causes a cascade of kinase activation, with Raf activating the mitogen-activated protein kinase kinases (MAPKK, or MEK) and MEK activating the ERK MAPK, which then translocates to the nucleus to phosphorylate and activate transcription factors to carry out the ...

RAS and its downstream cascades transmit cellular signals, resulting in increased transcription of genes involved in cell growth and division. Protein-coding gene targets of RAS signaling have been characterized extensively, but long noncoding RNAs (lncRNA) regulated by these processes have not. Using a custom-designed lncRNA microarray, we identified the lncRNA Orilnc1 as a genetic target of RAS that is critical for RAS oncogenicity. Orilnc1 expression was regulated by RAS-RAF-MEK-ERK signaling via the transcription factor AP1. Orilnc1 was highly expressed in BRAF-mutant cancers, such as melanoma. Silencing of Orilnc1 blocked tumor cell proliferation and growth in vitro and in vivo. In addition, Orilnc1 blockade reduced expression of cyclin E1 and induced G1-S cell-cycle arrest in tumor cells. Taken together, our results identify Orilnc1 as a novel, nonprotein mediator of RAS/RAF activation that may serve as a therapeutic target in RAS/RAF-driven cancers. Cancer Res; 77(14); 1-13. ©2017 AACR. ...

The catalytic p110 subunits of class 1 phosphoinositide 3-kinases (PI3Ks) have a conserved Ras binding domain (RBD), and an interaction has been noted between Ras guanosine triphosphatase (GTPase) and p110 PI3K in vitro and in overexpression systems. However, the biological relevance of this putative regulatory input has been unclear. Two groups now report a physiological role for Ras interactions with PI3K in flies and mouse neutrophils. Orme et al. created transgenic flies carrying a Dp110 (the only Drosophila p110) with mutations in the RBD that did not interact with Ras (either Ras1 or Ras2) but was otherwise biochemically normal. This Dp110RBD rescued flies from lethal deletion of Dp110; however, the rescued flies were smaller and females exhibited reduced fecundity, laying 60% fewer eggs. Dp110RBD flies also had decreased activation of Akt in response to insulin in the brain and imaginal discs and decreased basal Akt activation in the ovaries. Although the interaction with Ras does not ...

Growth-factor deprived mCFU-E cells (5x106 cells per condition) and BaF3-EpoR cells (1x107 cells per condition) were stimulated with different Epo doses and absolute concentrations were determined for pEpoR (B), pAKT (C), ppERK (D). The scale for pS6 (E) was estimated in arbitrary units. GTP-Ras (F) and ppERK were determined upon stimulation with indicated, color-coded Epo doses. pEpoR was analyzed by immunoprecipitation followed by immunoblotting, GTP-Ras was analyzed after pulldown using a fusion protein harboring GST fused to the Ras binding domain of Raf-1 followed by detection by quantitative immunoblotting. For pAkt and ppERK, cellular lysates were subjected to quantitative immunoblotting. Calibrator proteins were used for EpoR, AKT, GTP- Ras and ERK to facilitate the conversion to nM concentrations. SED-ML simulations ...

This paper examines the influence of the RAF Kinase Inhibitor Protein (RKIP) on the Extracellular signal Regulated Kinase (ERK) singalling pathway through modelling in a Morkovian process algebra, PEPA. Two models of the system are presented, a readgent-centric view and a pathway-centric view. The models capture functionality at the level of subpathway, rather than at a molecular level. Each model affords a different perspective of the pathway and analysis. We domonstrate the two models to be formally equivalent using the timing-aware bisimulation defined over PEPA models and discuss the biological significance ...

The team of scientists from Cancer Research UKs Cambridge Research Institute made the unexpected discovery that BRAF, which is linked to around 70 per cent of melanomas and seven per cent of all cancers, is in fact controlled by a gene from the same RAF family called CRAF - which has also been linked to the disease.. It is hoped this surprising finding may help scientists improve a new generation of genetically targeted treatments for cancers including melanoma.. Faults in the BRAF gene can promote the growth of cancer cells via a pathway called the MAPK. This disruption causes cells to replicate uncontrollably, leading to tumours forming.. This study looked at a drug which represents an early version of a targeted treatment for malignant melanoma, the most dangerous form of skin cancer in patients. This drug - which targeted CRAF and to a lesser extent BRAF - wasnt successful in patients with melanoma, despite its early promise in laboratory studies.. By showing that CRAF can interact with ...

The Ras-Raf-MAP kinase signaling pathway is involved in control of cell proliferation and differentiation. The Raf kinase family includes A-Raf, B-Raf, and C-Raf. Each family member has three highly conserved regions (CR1-3). The N-terminal CR1 contains the Ras-GTP-binding domain. The CR2 contains a negative regulatory

GSK2118436 is a selective BRAF V600E inhibitor. BRAF encodes a proto-oncogene B-Raf also known as serine/threonine protein kinase B-Raf. It is critical in regulating the MAPK/ERK signaling pathway. BRAF mutations frequently occur in many human cancers. [1

Buy L779450 (CAS 303727-31-3), a potent Raf kinase inhibitor. Join researchers using high quality L779450 from Abcam and achieve your mission, faster.

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Major finding: CRAF has a direct role in mitosis that does not require the RAF effector MEK.. Mechanism: CRAF interacts with PLK1 and promotes its activity and accumulation at kinetochores.. Impact: Allosteric RAF inhibitors that block phospho-Ser338 CRAF may be effective cancer therapies.. ...

GW 5074 is a potent, cell-permeable, reversible, and ATP-competitive cRAF1 kinase inhibitor (IC50 = 9 nM). It shows ≥100-fold selectivity for Raf kinase versus Cdk1, Cdk2, c-Src, ERK2, MEK, p38, Tie2, VEGFR2, and c-Fms.[

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Since 2008, the high-quality level measuring instruments of the KSR KUEBLER Niveau-Messtechnik GmbH in Zwingenberg have been part of the WIKA portfolio.