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Mutated BRAF activates ERK. 93 / 93
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"Class II BRAF mutants form stable and active dimers independent of RAS stimulation, and the kinase activity of Class II BRAF mutants typically falls between WT- BRAF and Class I BRAF mutants.Class III[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Small molecule inhibitors of mutant BRAF were developed to block protein kinase activity and prevent activation of MAPK and ERK signaling in tumor cells (XREF_FIG)."
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"Overexpression of this BRAF mutant (BRAF-A481F and AAAA) did not stimulate ERK activation suggesting that these residues are critical for the ability of kinase-dead BRAF to stimulate ERK."
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"In HEK293T cells, Trametinib modestly decreased ERK activity induced by BRAF mutations conferring elevated kinase activity while strongly inhibited kinase impaired BRAF and CRAF induced ERK activation."
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"The missense BRAF mutation that results in a valine (V) to glutamic acid (E) substitution at codon 600 (BRAF p.V600E) constitutively activates MAPK/ERK pathway [21] (Figure 1B)."
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"A number of the BRAF mutations that have been identified in melanoma, including D594V, G596R and G466V, do not activate the catalytic activity of BRAF, but do result in activation of MEK and ERK."
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"BRAF mutations are present in about 50% of melanomas, causing an over-activation of the MAPK and ERK pathway involved in cell proliferation and survival."
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"Next, to evaluate a potential interplay between mutant BRAF-induced ERK1/2 signaling and BMP-induced SMAD signaling pathways in the melanoma, we analyzed patient survivals as a function of high versus low expression of BMP1, BMP2, and BMP6 in two patient groups: BRAF mutant and BRAF-wildtype."
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"Accordingly, the present data show an inverse correlation between the activities of MEK-ERK-RSK signaling and AMPK in BRAF V600E CRC cells, suggesting that BRAF mutations activate phospho-MEK, Erk, and p90RSK without activating AMPK (XREF_FIG upper panel) and that inhibition of BRAF using selective BRAF inhibitors leads to inactivation of phospho-MEK, Erk, and p90RSK and activation of AMPK (XREF_FIG lower panel)."
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"This result may explain why H1666 and H508 cells are more sensitive to Trametinib than to Selumetinib, as BRAF mutations in these cell lines activate the ERK pathway in a CRAF dependent manner, similarly to KRAS mutated cells."
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"Ikenoue et al. [XREF_BIBR] indicated that the BRAF mutations of CRC can promote the activation of ERK, which activates downstream transcription factors to induce a range of biochemical processes including cell differentiation, proliferation, growth, while acting as the inhibitor of apoptosis."
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"COT overexpression represents another mechanism for resistance: lesions that cause the mutant BRAF-independent activation of ERK signaling."
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"In the BRAF mutant cells, AKT and ERK are regulated by similar positive and negative pathways as that in the KRAS mutant cells, except that ERK is activated by the mutant BRAF instead of KRAS."
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"Mutant BRAF led to deregulated activation of downstream MEK and ERK effectors in melanoma patients."
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"Class III BRAF mutations result in a weaker ERK activation compared to class I and class II mutations."
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"These BRAF mutations exhibit impaired kinase activity but induce ERK signaling by dimerizing with and activating CRAF."
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"BRAF mutation activates the MAPK/ERK pathway, resulting in an increase in some nuclear transcription factors."
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"The most common oncogenic BRAF mutation in melanomas, V600E (formerly called V599E), results in constitutive ERK signalling in vivo and can transform immortal fibroblasts (Davies et al, 2002) and immortal mouse melanocytes (Wellbrock et al, 2004)."
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"Pratilas et al. evaluated ERK dependent transcriptional output and feedback signaling in tumor cells in which ERK signaling is driven by mutant BRAF and in tumor cells in which ERK is driven by upstream receptors like EGFR or HER2."
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"While RAF proteins activate ERK signaling as homo- and heterodimers in the presence of active RAS, mutant BRAF can activate ERK signaling independently of RAS as an active monomer [10,11], and promote insensitivity to ERK negative feedback mechanisms [12]."
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"Thus, ERK signalling driven by low activity or kinase-dead BRAF mutants is RAS dependent and regulated by upstream signalling."
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"Melanoma cells are frequently characterized by oncogenic BRAF mutations that cause the constitutive activation of the MAPK/ERK mitogenic pathway, resulting in increased cell proliferation [1,2]."
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"BRAF mutations activate the MAPK/ERK pathway, and upregulate cellular proliferation and survival, thereby setting the stage for subsequent neoplastic transformation."
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"This result is consistent with the result seen in mice, again, it suggests that FAK is not involved in the regulation of KRAS-mutant CRCs.In mice, mutant BRAF-induced ERK activation is cancer stage-dependent with significantly higher levels of phosphorylated ERK in high-grade dysplasia and carcinoma (Rad et al., 2013), suggesting that different tumor stages may require different levels of p-ERK."
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"The BRAF mutation activates the MEK and ERK pathway by means of its effectors, which are the production and promotion of the malignant phenotype through genetic expression and proliferation [XREF_BIBR]."
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"These data indicate that RBJ may provoke MEK and ERK activation initiated either by Ras / Braf mutations or by other upstream signals activating MEK and ERK."
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"Moreover, BRAF mutation [ 18 ], PIK3CA mutation [ 19 ], PTEN deletion [ 20 , 21 ], and NF-1 deletion [ 22 ] are reported to promote cell proliferation and metastasis by directly activating the downstr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The current study is the first demonstration that mutant BRAF-induced activation of ERK signaling is tuneable in vivo, and by tuning ERK activation to alter the suppressive barrier, FAK regulates BRAF transforming activity.In BRAF-mutated melanoma, a complete shutdown of the MAPK pathway is necessary for significant tumor response (Bollag et al., 2010)."
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"KRAS and BRAF mutations were significantly correlated to early stage (I/II), grade (p = 0.004), histotype (p = 0.0014), and activated ERK (p < 0.001) [16]."
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"These BRAF mutants have been categorized into 3 subgroups by the molecular features with their oncogenic ability to activate downstream ERK signaling [16] ."
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"Approximately 50% of cutaneous melanomas harbor the BRAF mutations, which trigger excessive activation of MEK/ERK signaling, leading to cell proliferation and immune escape."
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"However co-expression of class 3 BRAF mutants with wild-type CRAF in these cells induced ERK signalling (XREF_FIG)."
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"A recent study demonstrated that the MAPK/ERK signaling pathway activated by the BRAF mutation was able to induce epigenetic aberrations by H3K27me3 and MYC [44]."
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"However, despite being highly anticipated , the existence of in vivo intrinsic fine-tuning of mutant BRAF-induced ERK activation has never been experimentally examined."
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"Furthermore, certain BRAF V600E -mutant melanomas and colorectal carcinomas appear to develop a dependence or ' addiction ' to Bim repression, since inhibition of mutant BRAF driven ERK1/2 signalling results in Bim accumulation and Bim mediated apoptosis."
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"In more than 50% of cutaneous melanomas, the BRAF mutation activates the MAP kinase/ERK signaling pathway."
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"This result is consistent with the result seen in mice, again, it suggests that FAK is not involved in the regulation of KRAS-mutant CRCs.In mice, mutant BRAF-induced ERK activation is cancer stage-dependent with significantly higher levels of phosphorylated ERK in high-grade dysplasia and carcinoma , suggesting that different tumor stages may require different levels of p-ERK."
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"10 One of the most common genetic alterations found in approximately 40-50% of melanomas is the constitutively activating mutation of the Braf serine/threonine kinase, which leads to unchecked stimulation of the mitogen activated kinase and extracellular signal regulated kinase (MEK) and extracellular signal regulated kinase (ERK) pathway."
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"However, despite being highly anticipated (Brandt et al., 2019), the existence of in vivo intrinsic fine-tuning of mutant BRAF-induced ERK activation has never been experimentally examined."
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"BRAF mutations activate ERK and MAPK, leading to a series of cellular responses."
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"BRAF mutation can activate the MEK/ERK pathway, which increases cell proliferation and inhibits apoptosis [16]."
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"BRAF mutations drive constitutive activation of the MAPK/ERK pathway independently of RAS activity and promote malignant biological activities of cancer cells [15]."
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"These data suggest that in some class 2 BRAF mutants, while mutant BRAF activates ERK, an additional contribution to ERK activation can come from upstream signaling."
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"The current study is the first demonstration that mutant BRAF-induced activation of ERK signaling is tuneable in vivo, and by tuning ERK activation to alter the suppressive barrier, FAK regulates BRAF transforming activity.In BRAF-mutated melanoma, a complete shutdown of the MAPK pathway is necessary for significant tumor response ."
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"Activating BRAF mutations and fusion products constitutively activates the MAPK/ERK pathway (also known as the RAS-RAF-MEK-ERK pathway) that communicates receptor signaling to the DNA in the nucleus of the cell [23]."
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"This suggests that KRAS and BRAF mutations activate downstream ERK signaling in a partially autonomous manner."
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"The study results revealed that most melanoma patients carry BRAF mutations that may activate the MAPK/ERK signaling pathway [94]."
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"Somatic BRAF mutation, which makes the BRAF oncogene, can enhance the MAPK/ERK pathway and contribute to the occurrence and development of malignant tumors."
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"The BRAF mutation activates the MEK/ERK signaling pathway, promoting tumor cell proliferation and survival [5]."
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"Whether mult-HCL has entirely by passed any requirements for BCR, possibly due to mutant BRAF constitutively activating the ERK1/2 pathway, remains at present speculative."
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"To investigate the effect of Dabrafenib on ERK signaling induced by different BRAF mutations, we transiently expressed 13 BRAF mutants singly or with CRAF in HEK293T cells; we then evaluated the ERK activation status after 2 h of Dabrafenib treatment (2.5 muM)."
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"It is believed that mutant BRAF permanently activates downstream MEK and ERK, with or without the activation of upstream RAS."
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"Singly, Dabrafenib only weakly suppresses mutant BRAF induced ERK signaling and can induce ERK paradoxical activation in CRAF overexpressing cells."
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"Experimental evidence has suggested that BRAF mutations cause BRAF kinase activity and increased ERK signaling, leading to cell proliferation in melanoma cells (Davies et al., 2002; Dong et al., 2003;[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"WNT signalling is known to play a crucial role in thyroid carcinogenesis, and several mechanisms of its deregulation have been described, including inhibition of the β-catenin degradation complex via its phosphorylation by RET/PTC, inhibition of E-cadherin expression through the MAPK/ERK pathway activated by BRAF mutations, and activation of both canonical and non-canonical Wnt pathways by RAS mutations ."
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"BRAF mutations are known to activate ERK and should not be classified as wild-type Ras."
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"Commonly found BRAF mutants stimulate constitutive RAF and MEK (mitogen activated ERK activating kinase)/ERK (extracellular signal regulated kinase) pathway activation and act as transforming oncogenes in NIH-3T3 cells and immortalized murine melanocytes."
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"BRAF mutation increases the kinase activity of BRAF by nearly 700-fold, thereby stimulating constitutive activation of MEK/ERK signaling in tumor cells in the absence of extracellular stimuli, allowing the cell to become self-sufficient in growth signals within this pathway (28)."
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"This finding may also be particularly relevant to PTC since the BRAF mutation in PTC is known to activate ERK1/2 pathway, which results in the transformation and the proliferation of thyrocytes ( Niki[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"BRAF mutations activate the MAPK/ERK signaling pathway."
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"XREF_BIBR, XREF_BIBR BRAF mutations increase MEK and ERK activity, promoting tumour proliferation and growth."
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"BRAF mutations constitutively activate ERK signaling through hyperactivation of the RAS-ERK pathway, resulting in enhanced cell proliferation and survival (Brose et al., 2002; Naoki et al., 2002)."
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"ERK activation by activated BRAF mutants causes feedback inhibition of RAS activity, whereas ERK activation by ARAF mutants does not."
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"Studies have shown that the BRAF mutation can activate the MAPK/extracellular signal-regulated kinase (ERK) pathway, which in turn upregulates genes involved in glycolysis and glutaminolysis, leading to an increase in glucose and glutamine uptake and utilization in PTC cells [44]."
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"Indeed, the persistent expression of mutant BRAF was responsible for rebound activation of ERK, as the addition of a BRAF V600E inhibitor or specific knockdown of mutant BRAF inhibited reactivation of ERK after treatment with AUY922."
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"XREF_BIBR, XREF_BIBR While inhibitors of mutant BRAF monomers suppress the ERK signaling, they relieve ERK dependent negative feedback and reactivate ligand dependent EGFR and RAS signaling upon wild-type RAF dimers in melanoma cells."
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"Constitutive ERK1/2 activation, by mutant BRAF or KRAS, provokes mitochondrial translocation of PGK1 which phosphorylates PDK1 and contributes to aerobic glycolytic switch in cancer [ 44 ]."
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"The BRAF mutation ignites constitutive activation of the MAPK signal transduction and augments ERK output."
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"BRAF is a serine/threonine-protein kinase, and these BRAF mutations constitutively activate BRAF kinase activity and the downstream ERK pathway [4]."
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"Aberrant cell cycle related proteins such as Cyclin D1 has been shown to be reversible using chemical inhibitors suggesting that expression is not a constitutive disease trait but elicited by MEK and [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In melanoma cells, MEK and ERK1/2 can be activated by active mutations of BRAF in 2D cultures."
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"Dr. Thakur 's reason that if vemurafenib were withheld at this point the extra ERK stimulating signal from new liberated mutant BRAF might cause ERK is an effective as under active ERK for shutting cell cycle down."
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"In about half of all melanoma patients, tumor growth is driven by gain-of-function mutations of BRAF (v-rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation."
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"BRAF mutation activates ERK1/2 which in turn up-regulates Brn-2, a molecule highly over-expressed in BRAF mutant melanoma cells, but not in melanocytes or melanoblasts XREF_BIBR."
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"Kinase-active Mutant BRAF induces MEK and ERK pathway activation in HEK293T cells."
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"These differences suggest that although both BRAF mutation and the RET and PTC1 rearrangement are able to activate the MEK and ERK signal transduction pathway, other pathways not affected by PD0325901 may be involved in PTC cells with the RET and PTC rearrangements."
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"Mutant BRAF constitutively activates the downstream kinases, MEK and ERK, within the mitogen activated protein kinase (MAPK) pathway, leading to uncontrolled cell proliferation."
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"Activated BRAF mutants that activate ERK and not PI3K had not yet been identified in human tumors, but their work predicts that if such mutants existed, they would stimulate proliferation but not induce membrane ruffling or actin reorganization."
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"Do all BRAF mutations induce constitutive ERK activation?"
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"The kinase activity of BRAF mutants is hyperactivated and drives elevated ERK signaling output accompanied by exaggerated ERK-dependent feedback inhibition of upstream signaling, including that of RTKs and WT RAS-activated pathways."
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"Further, investigators have shown that most BRAF mutants with reduced kinase activity can still activate MEK and ERK via transactivation of CRAF."
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"BRAF mutations trigger the constitutive activation of the MAPK/ERK signaling pathway, promoting uncontrolled cell proliferation and tumor survival (Johnson and Dahlman, 2018)."
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"Paradoxically, most BRAF mutants with reduced kinase activity still activate MEK and ERK via transactivation of CRAF."
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"Activated BRAF mutants that activate ERK and not PI3K had not yet been identified in human tumors, but their work predicts that if such mutants existed, they would stimulate proliferation but not induce membrane ruffling or actin reorganization."
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"We conclude that, whereas hyperactivation of ERK signaling by oncogenic BRAF mutants is sufficient to deregulate cell proliferation, ERK-dependent feedback inhibition of RAC1 suppresses migration."
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"A clinically relevant dose of Dabrafenib, a type I RAF-inhibitor, in HEK293T cells reduced ERK activity induced by BRAF mutations conferring high kinase activity in the presence and absence of CRAF."
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"The overexpression of Kidins220 resulting in sustained activation of MEK and ERK signalling rather than BRAF mutation, has been identified as leading to acral lentiginous melanoma tumourigenesis."
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"These results suggest that L525R cells are more sensitive to selumetinib than V600E cells, though both BRAF mutants equally activate ERK."
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"Mutant BRAF triggers constitutive activation of the MAPK and ERK pathway and is typically mutually exclusive of activating RAS mutations in tumors [XREF_BIBR, XREF_BIBR]."
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"The most general BRAF mutation in thyroid cancer, V600E, initiates the MAPK/ERK pathway which encourages cell growth and survival [ 38 ]."
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"Furthermore, Dabrafenib also inhibited ERK activity induced by BRAF mutants conferring impaired kinase activity co-expressed with CRAF."
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"The constitutive activation of the MEK/ERK pathway induced by BRAF mutations is required for the proliferation, resistance to apoptosis and invasion of melanoma cells [4–6] ."
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"The most common BRAF mutation (BRAF V600E), found in about 8% of human tumors and more than 50% of melanomas, results in ERK signaling upregulation, independent of RAS activity."
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