IndraLab
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"The study suggests that multiple factors contribute to the transition and maintenance of the IDTC state and from these observations it is tempting to speculate that the burden of signaling is distributed between multiple pathways unlike the parental BRAF mutant cells, which seem to be primarily dependent on BRAF driven ERK signaling."
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"Similarly, while a kinase-defective form of human B-RAF (B-RAF A481F) very modestly activated ERK signalling when co-transfected with a B-RAF receiver (B-RAF AAAA), the same kinase-defective B-RAF mutant strongly activated ERK signalling through the B-RAF receiver when combined to the R506E mutation (Fig. 9d lane 6 mutant hB-RAF A481F R506E +hB-RAF4A)."
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"Available data suggest that the most frequent mutational events in these carcinomas are mutations in B-RAF, leading to activation of the RAF and MEK (mitogen activated protein and extracellular signal regulated kinase (ERK) kinase)/ERK pathway and in phosphoinositide 3-kinase (PI3K)/AKT signalling."
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"This may result from mutational activation of components of the downstream signaling pathways, such as PIK3CA or BRAF, that directly activate the PI3K and AKT and MEK and ERK pathways, respectively, or activation of another RTK that sustains downstream signaling despite inhibition of the oncogenic RTK."
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"6 Unfortunately, first and second generation BRAFi can not be used as single agents to treat NRAS-mutant melanoma because while these inhibitors are effective at shutting down ERK signaling mediated by mutant-BRAF, they paradoxically upregulate ERK activity in the presence of oncogenic RAS, by stimulating BRAF-CRAF heterodimerization."
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"BRAF drives tumorigenesis through constitutive downstream ERK1/2 activation , but hyperactivation of ERK induced by oncogenic BRAF is not tolerated in the intestine: high ERK activation, induced by transgenic expression of oncogenic BRAF (BRAF ) or by activation of two BRAF alleles in BRAF mutant mice, engages tumor suppressive mechanisms, causing loss of stem cells and induction of differentiation and senescence ."
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"One was the highly aggressive triple negative (ER -, PR - and HER2 -) MDA-MB231 cell line, which carries oncogenic mutations in KRAS and BRAF genes, shows enhanced PKCtheta activity and accumulates high levels of Fra-1 as a result of stabilizing phosphorylations by both KRAS- and BRAF activated Erk pathway kinases and PKCtheta."
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"Nevertheless, the antitumor role of DSF/Cu in thyroid cancer and its effect on the response of BRAF -mutated thyroid cancer cells to PLX4032 have not yet been investigated.In this study, we demonstrate that DSF/Cu can kill BRAF -mutated thyroid cancer cells and improves their cellular response to BRAF kinase inhibitor by relieving feedback activation of MAPK/ERK and PI3K/AKT pathways in an ROS-dependent manner."
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"Overexpression of either WT BRAF or WT CRAF (8~ 15-fold increases over endogenous concentrations) in NIH3T3 cells, caused small increases in ERK signaling but had little or no effect on cellular RAS-GTP (Figure 2A) By contrast, increasing WT ARAF caused a concentration-dependent increase in RAS-GTP accompanied by a decrease in ERK signaling (Figure 2A and 2B)."
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"The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen activated protein and extracellular signal regulated kinase MEK1 and MEK2, all belonging to the same RAS-extracellular signal regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis."
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"The Food and Drug Administration has approved the Serine/threonine-protein kinase B-raf (BRAF) inhibitor and Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor combo as the first-line treatment for individuals with metastatic melanoma, although the majority of these patients exhibit primary or secondary drug resistance in the clinic."
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"Using a panel of melanoma cell lines derived from the establishment of excised primary and metastatic tumours, we have investigated the ability of dabrafenib to both exert an antiproliferative activity on cultured melanoma cells and block the ERK signalling induced by the mutated BRAF."
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"BRAF-induced MAPK-ERK activation may not be controlled with MEK inhibition only, and may require combined MEK and BRAF inhibition, whereas the MAPK-ERK activation can be modulated with MEK inhibition alone more readily in RAS-mutation-initiated cancers [ xref , xref , xref ] ( xref )."
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"BRAF drives tumorigenesis through constitutive downstream ERK1/2 activation (Wellbrock et al., 2004), but hyperactivation of ERK induced by oncogenic BRAF is not tolerated in the intestine: high ERK activation, induced by transgenic expression of oncogenic BRAF (BRAF ) or by activation of two BRAF alleles in BRAF mutant mice, engages tumor suppressive mechanisms, causing loss of stem cells and induction of differentiation and senescence (Riemer et al., 2015; Tong et al., 2017)."
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"Indeed, the oncogenic activation of BRAF drives the inappropriate activation of ERK signaling and the deregulation of cell proliferation [XREF_BIBR], and is responsible for the inhibition of the mitochondrial apoptotic pathway [XREF_BIBR - XREF_BIBR], the latter being consistent with the apoptosis resistant phenotype of BRAF driven cancer cells."
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"TMRM and calcein‐AM staining showed that opening of the mitochondrial permeability transition pore (mPTP) during STS‐induced cell death could be significantly inhibited by BRAF V600E. Moreover, our study demonstrated that BRAF V600E constitutively activates mitochondrial ERK (mERK) to inhibit GSK‐3‐dependent CypD phosphorylation, thereby making BRAF V600E mutant tumour cells more resistant to mPTP opening."
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"Furthermore, we report that mitochondrial ERK is constitutively activated by mitochondrial localization BRAF V600E, which inhibits GSK‐3‐dependent phosphorylation of mitochondrial chaperone cyclophilin D(CypD), making it more difficult for BRAF V600E mutant papillary and anaplastic thyroid cancer cells to open mPTP, so that they are less prone to cell death."
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"Dabrafenib, an inhibitor of RAF-1 and B-RAF, suppressed the early activation of ERK, but a significant amount of phosphorylated ERK remained after 60min of shaking in the presence of dabrafenib (XREF_FIG A), which gradually increased over time only when FSS was applied (XREF_FIG C)."
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"In a majority of human cancers, the PI3K and AKT pathway is frequently activated by the activating mutations of PI3K p110alpha (PIK3CA) and the loss or inactivating mutation of PTEN, whereas hyper activation of MEK and ERK signaling driven by mutant RAS and BRAF is also a common oncogenic event in a variety of cancers [XREF_BIBR, XREF_BIBR]."
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"The observation that kinase-dead BRAF was able to activate ERK signaling through dimerizing with and activating CRAF provided further support for the role of RAF dimerization and raised awareness that catalysis-dependent and -independent functions of RAF are functionally important [103, 217, 218]."
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"This single base substitution leads to the replacement of the amino acid valine (V) in position 600 with a glutamate (E) leading to constitutive activation of the BRAF protein which subsequently results in the constitutive activation of the downstream components MEK and ERK1/2 (14)."
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"These included B-RAF which activates ERK via MEK1/2 directing cell proliferation, as well as MLK-like mitogen-activated protein triple kinase (MLTK) which can activate JNK-mediated pathway regulating actin organization, and has been shown to be an upstream MAP3K in stress induced by the ribotoxinsanisomycin, ricin and Shiga toxin ( xref ; xref )."
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"Interestingly, Vemurafenib treatment increased both the intrinsic kinase activity of endogenous ARAF ( xref ) and ERK activation ( xref ) in double BRAF- and CRAF-deficient resistant cultures, demonstrating that ARAF homodimers are sufficient to sustain ERK paradoxical activation by BRAF inhibitor in the absence of other RAF proteins."
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"With respect to BRAF inhibitors, the observation that BRAF selective agents activate ERK signaling in non-BRAF-mutated tumors raises the concern that not only would these agents not be effective in CS or CFC, but they may be contraindicated in non oncology settings by promoting the growth of keratoacanthoma skin lesions."
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"Last, while we focused on the most common BRAF mutant, BRAF-V600E, other BRAF variants that also activate ERK (13, 28), may confer distinct phenotypes on CMs based on specific ERK activation levels.In summary, we have shown that BRAF-V600E–mediated ERK activation in NRVMs can induce sustained or reversible changes in cell cycling, function, glycolysis, and migratory capacity."
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"► BRAF activates ERK but in some circumstances BRAF inhibitors can induce tumor growth ► BRAF inhibitors drive BRAF-CRAF binding, activating ERK in cells with oncogenic RAS ► Kinase-dead mutants of BRAF have the same effect as BRAF inhibitors ► Oncogenic RAS and kinase-dead BRAF cooperate to induce melanoma in mice"
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"In this scenario, loss of BRAF signalling is predicted to reduce cardiomyocyte hypertrophy and interstitial fibrosis as, indeed, it does.As an α -adrenergic receptor agonist phenylephrine acts directly on cardiomyocytes to promote hypertrophy (Figure 9B), but the signal to hypertrophy is propagated by transactivation of one or more of the insulin receptor family, signalling via PI3K and PKB/Akt rather than ERK1/2 [29]."
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"Tumorigenesis assays by subcutaneous transplantation of organoids in NSG mice showed that cells harboring only the BRAF V600E mutation or Apc or Ctnnb1 mutations were not able to form tumors indicating the requirement of the combination of MEK-ERK activation by BRAF V600E along with Wnt activation for tumorigenesis (Fig. xref )."
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"In melanoma cells harboring the NRAS mutation, the mutated NRAS protein needs CRAF to activate the MEK and ERK pathway XREF_BIBR, and the BRAF protein is phosphorylated by ERK on S151 near the RAS binding domain, which results in the inhibition of the NRAS and BRAF interaction XREF_BIBR."
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"We next determined whether the activity of BRAF and V600E is also altered as their stability upon truncation of C-terminal tail, and found that their mutants without C-terminal tail triggered a much stronger ERK signaling when expressed in 293T cells at a comparable level (Figure 1C and Figure S1C)."
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"Conversely, ERK-nKTR is excluded from the nuclei of all VPCs when MPK-1 and ERK is activated by uniform expression of a highly active and stable form of LIN-45 and Braf in all VPCs (transgene arTi31, see STAR Methods), (XREF_FIG), similar to the phospho-mimetic ERK-nKTR (EEE) (XREF_FIG)."
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"Our results suggest that : (i) extracellular signal regulated kinase is activated by B-Raf in response to a calcium sensitive adenylate cyclase; and (ii) extracellular signal regulated kinase activates casein kinase-2 via a protein phosphatase (s) that may be of the PP1 and/or PP2A type."
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"The identification of BRAF driver mutations in melanoma has led to the development of specific inhibitors targeting the extracellular-signal-regulated kinase (ERK) pathway, which have high response rates and improve survival in patients with BRAF-mutant advanced melanoma and those at high risk of recurrence XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"Absence of RAS expression abrogated ERK activation by BRAF F247L and R558Q but had no effect on ERK activation by BRAF L485F and L525R. Based on these data, BRAF A33T was considered to have no effect on ERK signaling, BRAF F247L and R558Q were classified as class 3 mutants, and BRAF L525R and L485F were classified as class 2 mutants."
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"Using this vector in a murine syngeneic BM transplantation model for BCR-ABL-induced chronic myeloid leukemia, we find that oncogene expression and target knockdown in primary hematopoietic cells with this vector is efficient both in vitro and in vivo, and demonstrate that Raf1, but not BRAF, modulates BCR-ABL-dependent ERK activation and transformation of hematopoietic cells."
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"XREF_BIBR This genetic alteration of BRAF sequentially induces constitutive extracellular signal regulated kinase (ERK) signaling through a hyperactivation of the RAS/RAF/mitogen activated protein kinase and ERK (MAPK and ERK) pathway that is involved in promoting the proliferation, survival and development of tumor cells."
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"[XREF_BIBR] The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen activated protein and extracellular signal regulated kinase MEK1 and MEK2, all belonging to the same RAS extracellular signal regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis."
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"The increased apoptosis, observed in human melanoma cell lines when BRAF expression is downregulated using RNA interference, supports a role for oncogenic BRAF driven MEK and ERK overactivation in maintaining the transformed phenotype of malignant melanoma cells (Hingorani et al, 2003; Karasarides et al, 2004)."
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"Furthermore, Notarangelo and colleagues reported that the exposure of thyroid cancer cells to vemurafenib resulted in a rapid feedback activation of EGFR pathway, and dual EGFR and BRAF blockade induces suppression of ERK signaling, inhibition of cell proliferation, and synthetic lethality [71]."
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"c-Raf is thought to be responsible for the transient activation of the ERK pathway required for proliferation upon epidermal growth factor stimulation, while B-Raf causes a persistent activation of ERK required for differentiation in response to stimulation with nerve growth factor [XREF_BIBR], consistent with our observations."
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"Thus, it is urgent to find strategies to solve the resistance of BRAF kinase inhibitors.It has been demonstrated that the dual EGFR/HER-2 kinase inhibitor lapatinib sensitizes BRAF-mutant thyroid cancers to BRAF kinase inhibitors by blocking the rebound of MAPK/ERK pathway and the activation of the PI3K/AKT pathway [16]."
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"This pathway is driven by hypermethylation of genes and is characterized by the presence of protooncogene BRAF (protein kinase B-Raf), which causes increased MAPKs and ERKs (mitogen activated protein kinases and extracellular signal regulated kinases) signaling, leading to increased cell proliferation, cell division, and secretion [XREF_BIBR]."
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"Binding of extracellular growth factor to receptor tyrosine kinase (RTK) activates BRAF, which subsequently triggers the RAS-BRAF-MAPK/extracellular signal-regulated kinase (ERK) signaling pathway, leading to cell growth, proliferation, anti-apoptosis, and angiogenesis, among other processes [1617]."
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"This is reminiscent of the paradoxical MAPK activation observed BRAF-selective kinase inhibitors in BRAF-mut cancer models, whereby a kinase-inhibited BRAF protein is still able to form complexes with CRAF or yet unidentified interactors and paradoxically activate MEK and ERK downstream (10, 18, 19)."
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"Although BRAF-selective inhibitors block ERK signaling in tumors with BRAF mutation, they paradoxically activate ERK signaling and accelerate the growth of tumors with wild-type (WT) BRAF or with RAS mutations [10–12], thereby limiting the usefulness of BRAF inhibitors as a cancer therapy."
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"Receptor tyrosine kinase-ROS interactions
of the MAPK signaling pathway activate Ras proteins, which in turn
activate B-Raf kinase, which in turn activates ERK, JNK, or p38, and
activation of ERK or JNK leads to the synthesis of MITF, which subsequently
up-regulates melanogenesis-associated proteins and promotes melanin
synthesis, or may increase the production of MITF through the NF-kB
signaling pathway increases the expression of pro-inflammatory cytokines
such as TNF-α, which modulates the inflammatory response and
activates melanocytes. xref Therefore, we
hypothesized that salvianolic acid B may improve melasma by increasing
the body’s antioxidant capacity and inhibiting the inflammatory
response."
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"The combination of the B-raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors (BRAFi + MEKi) impeded the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade in melanoma cells, which induced the activation of caspase-3 and resulted in GSDME-executed pyroptosis as well as extravasation of DAMPs (132)."
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"Direct ERK1/2 inhibition is considered a promising approach to avoid ERK1/2 reactivation caused by upstream kinases BRAF, MEK1/2, and KRAS, as well as by receptor tyrosine kinase inhibitors, but the dynamics and selectivity of ERK1/2 inhibitors are much less studied compared with BRAF or MEK inhibitors."
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"For instance, increased cell invasion can be mediated by the BRAF mutation-induced activation of phosphorylated extracellular-signal-regulated kinase (pERK), phosphorylated mitogen-activated protein kinase (pMEK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and metalloproteinases activity [ xref ]."
| PMC
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"Since the BRAF KE mutation induces more marked increases in ERK activity and more severe cognitive disabilities in RASopathy patients, we deemed it worthy of investigation in hopes that the identification of the neurobiological disease mechanisms triggered by this mutation will contribute to our understanding of the cognitive impairments associated with RASopathies."
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"One such candidate is BRAF (v-raf Murine Sarcoma Viral Oncogene Homolog B1), a gene, responsible for production of the B-Raf protein, a member of the Raf serine/threonine kinase family. xref BRAF is a key mediator in the mitogen activated protein kinase (MAPK) cell signaling pathway, which has a role in cell proliferation, survival, and differentiation. xref B-Raf activates MAPK extracellular signal-regulated kinase (MEK) proteins, which stimulate extracellular signal-regulated kinase (ERK) proteins which control cellular responses. xref "
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"To determine whether dnMEK1 can prevent BRAF KE–induced overactivation of RAS/ERK signaling and the subsequent aberrantly hyperactive Ca fluctuations in hippocampal astrocytes, we injected GFAP–BRAF KE or GFAP-BRAF WT virus together with AAV5-GFAP-HA-dnMEK1 (GFAP-dnMEK1) virus or saline into the dorsal CA1 region of the hippocampus."
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"This is reminiscent of the paradoxical MAPK activation observed BRAF-selective kinase inhibitors in BRAF -mut cancer models, whereby a kinase-inhibited BRAF protein is still able to form complexes with CRAF or yet unidentified interactors and paradoxically activate MEK and ERK downstream ( xref , xref , xref )."