scholarly journals BRAF: A Two-Faced Janus

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2549
Author(s):  
Pasquale Pisapia ◽  
Francesco Pepe ◽  
Antonino Iaccarino ◽  
Roberta Sgariglia ◽  
Mariantonia Nacchio ◽  
...  
Keyword(s):  
Braf Mutations ◽  
Extracellular Signal Regulated Kinase ◽  
Oncogenic Mutations ◽  
Extracellular Signal ◽  
Therapeutic Decisions ◽  
Protein Map ◽  
Thyroid Papillary ◽  
Mitogen Activated Protein ◽  
Murine Sarcoma ◽  
Viral Oncogene Homolog

Gain-of-function of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) is one of the most frequent oncogenic mutations in numerous cancers, including thyroid papillary carcinoma, melanoma, colon, and lung carcinomas, and to a lesser extent, ovarian and glioblastoma multiforme. This mutation aberrantly activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, thereby eliciting metastatic processes. The relevance of BRAF mutations stems from its prognostic value and, equally important, from its relevant therapeutic utility as an actionable target for personalized treatment. Here, we discuss the double facets of BRAF. In particular, we argue the need to implement diagnostic molecular algorithms that are able to detect this biomarker in order to streamline and refine diagnostic and therapeutic decisions.

scholarly journals A Rare p.T599dup BRAF Mutant NSCLC in a Non-Smoker

2020 ◽  
Vol 28 (1) ◽  
pp. 196-202
Author(s):  
Alla Turshudzhyan ◽  
James Vredenburgh
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Activating Mutations ◽  
Extracellular Signal ◽  
Activating Mutation ◽  
Mitogen Activated Protein ◽  
Murine Sarcoma

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) mutated non-small-cell lung cancer (NSCLC) is an exceptionally rare form of lung cancer, found only in one to two percent of patients with an NSCLC diagnosis. BRAF NSCLC traditionally affects former or active smokers. BRAF mutations have always been of special interest to the oncological community, as they offer potential for targeted therapies. BRAF mutation spectrum includes mutations that are of both V600 and non-V600 types. BRAF V600 is an activating mutation, which results in high kinase activity and overproduction of active oncoproteins such as rapidly accelerated fibrosarcoma (RAF). This makes them susceptible to targeted therapies with RAF inhibitors. There has been little evidence, however, regarding efficacy of RAF inhibitors towards non-activating mutations that have intermediate to low kinase activity, such as non-V600 BRAF mutations. While several approaches have been investigated to overcome the limitations of RAF inhibitors, such as use of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) inhibitors or combination of MEK and RAF inhibitors, none of them have been proven to have a superior efficacy for low kinase activity non-V600 BRAF tumors. We present a case of an extremely rare variant of NSCLC BRAF p.T599dup mutation in a non-smoker that responded to a targeted combination therapy with RAF and MEK inhibitors. The patient responded well to therapy that usually targets high kinase activity V600 mutations. Our hope is to bring more attention to non-V600 mutations and document their responses to existing and new therapies.

scholarly journals A Novel Regulatory Mechanism of Map Kinases Activation and Nuclear Translocation Mediated by Pka and the Ptp-Sl Tyrosine Phosphatase

1999 ◽  
Vol 147 (6) ◽  
pp. 1129-1136 ◽  
Author(s):  
Carmen Blanco-Aparicio ◽  
Josema Torres ◽  
Rafael Pulido
Keyword(s):  
Map Kinases ◽  
Nuclear Translocation ◽  
Tyrosine Phosphatase ◽  
Phosphorylation Site ◽  
Extracellular Signal Regulated Kinase ◽  
Inactive Form ◽  
Extracellular Signal ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Dependent Protein

Protein tyrosine phosphatase PTP-SL retains mitogen-activated protein (MAP) kinases in the cytoplasm in an inactive form by association through a kinase interaction motif (KIM) and tyrosine dephosphorylation. The related tyrosine phosphatases PTP-SL and STEP were phosphorylated by the cAMP-dependent protein kinase A (PKA). The PKA phosphorylation site on PTP-SL was identified as the Ser231 residue, located within the KIM. Upon phosphorylation of Ser231, PTP-SL binding and tyrosine dephosphorylation of the MAP kinases extracellular signal–regulated kinase (ERK)1/2 and p38α were impaired. Furthermore, treatment of COS-7 cells with PKA activators, or overexpression of the Cα catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38α by wild-type PTP-SL, but not by a PTP-SL S231A mutant. These findings support the existence of a novel mechanism by which PKA may regulate the activation and translocation to the nucleus of MAP kinases.

Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-κB-independent upregulation of Bcl-xL

2007 ◽  
Vol 292 (5) ◽  
pp. H2467-H2474 ◽  
Author(s):  
Rachel Zhande ◽  
Aly Karsan
Keyword(s):  
Endothelial Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Erythroid Progenitors ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Survival Pathway ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Endothelial Cell Death ◽  
Underlying Mechanisms

Erythropoietin (EPO) regulates the production of red blood cells primarily by preventing apoptosis of erythroid progenitors. More recently, however, EPO has emerged as a major cytoprotective cytokine in several nonhemopoietic tissues in the setting of stress or injury. The underlying mechanisms of the protective responses of EPO have not been fully defined. Here we show that EPO triggers a phosphatidylinositol 3-kinase-(PI3K)-dependent survival pathway that counteracts endothelial cell death. The protection conferred by PI3K relies on the subsequent induction of Bcl-xL, a prosurvival member of the Bcl-2 protein family. In addition, EPO counteracts the upregulation of the pro-apoptotic BH3-only protein BIM, which is induced by serum withdrawal. EPO also activates extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are involved in a Bcl-xL-independent cytoprotective pathway. EPO caused a prolonged activation of nuclear factor (NF)-κB, which was blocked by inhibition of PI3K, but not by inhibition of mitogen-activated protein (MAP)/ERK kinase (MEK), suggesting that EPO-activated NF-κB requires PI3K activity. However, the activation of the NF-κB pathway was not required for the ability of EPO to counteract endothelial apoptosis. Thus EPO promotes survival of endothelial cells through PI3K-dependent Bcl-xL-induction and BIM regulation, as well as through a separate mechanism involving the ERK pathway.

scholarly journals Mitochondrial-derived hydrogen peroxide inhibits relaxation of bovine coronary arterial smooth muscle to hypoxia through stimulation of ERK MAP kinase

2009 ◽  
Vol 297 (6) ◽  
pp. H2262-H2269 ◽  
Author(s):  
Qun Gao ◽  
Xiangmin Zhao ◽  
Mansoor Ahmad ◽  
Michael S. Wolin
Keyword(s):  
Map Kinase ◽  
Rho Kinase ◽  
Ros Generation ◽  
Extracellular Signal Regulated Kinase ◽  
Mitochondrial Superoxide ◽  
Mitochondrial Ros ◽  
Extracellular Signal ◽  
Protein Map ◽  
Arterial Relaxation ◽  
Mitogen Activated Protein

Mitochondrial reactive oxygen species (ROS) are potentially important in vascular oxygen-sensing mechanisms because hypoxia appears to be a stimulus for mitochondrial ROS generation; however, scavenging of endogenous ROS does not alter relaxation of endothelium-denuded bovine coronary arteries (BCA) to hypoxia. The purpose of this study was to investigate the influence of increasing mitochondrial ROS on the relaxation of BCA to hypoxia. Increasing mitochondrial superoxide with inhibitors of electron transport (10 μM rotenone and antimycin) and by opening mitochondrial ATP-dependent K+ channels with 100 μM diazoxide were observed in this study to attenuate relaxation of BCA precontracted with 30 mM KCl to hypoxia by 68–76% and 38%, respectively. This effect of rotenone is not prevented by inhibiting NADPH oxidase (Nox) activation or scavenging superoxide with Peg-SOD; however, it is reversed 85% and 26% by increasing the consumption of intracellular peroxide by 0.1 mM ebselen and 32.5 U/ml Peg-catalase. Because inhibition of extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase (10 μM PD-98059), but not src kinase or rho kinase, also reverses the effects of rotenone by 69%, the peroxide-elicited force-enhancing effects of ERK appear to be attenuating the response to hypoxia. Rotenone increased the phosphorylation of ERK (by 163%). Activation of ERK in BCA with 0.1 mM peroxide or endogenous peroxide generated by stimulating Nox2 with a stretch treatment or contraction with 100 nM U-46619 also attenuated relaxation to hypoxia. Thus coronary arterial relaxation to hypoxia may be attenuated by pathophysiological conditions associated with increased peroxide generation by mitochondria or other sources that stimulate ERK.

ERK5 and its role in tumour development

2012 ◽  
Vol 40 (1) ◽  
pp. 251-256 ◽  
Author(s):  
Pamela A. Lochhead ◽  
Rebecca Gilley ◽  
Simon J. Cook
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Invasion And Migration ◽  
Extracellular Signal Regulated Kinase ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Tumour Cell Invasion ◽  
And Migration

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the ‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.

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