Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of acute myeloid leukemia has not changed significantly over the last 40 years. Recent progress in understanding the biology of this disease and identification of driver mutations has ushered in a new era of molecular therapeutics. Although a number of molecular markers and pathways have been identified and may serve as potential therapeutic targets, the best studied amongst these include FMS like tyrosine kinase 3 (FLT3), RAS/RAF/MEK/ERK and Janus kinase (JAK-2). In this review we discuss the molecular biology of AML, with a special focus on the above mentioned pathways. We discuss novel molecular targeted therapies that are in preclinical and clinical development. These include AC-220, sorafenib and midostaurin in FLT3 mutated patients; GSK1120212 and MSC1936369B in RAS mutated patients; and INCB018424 in JAK2 mutated patients. Identification of such molecular mutations and appropriate use of targeted therapies, either alone or in combinations, may eventually revolutionize the treatment of AML.
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PMID:Molecular targeted therapy in acute myeloid leukemia. 2250 81

Protein kinase signaling is fundamental to cell homeostasis and is deregulated in all cancers but varies between patients. Understanding the mechanisms underlying this heterogeneity is critical for personalized targeted therapies. Here, we used a recently established LC-MS/MS platform to profile protein phosphorylation in acute myeloid leukemia cell lines with different sensitivities to kinase inhibitors. The compounds used in this study were originally developed to target Janus kinase, phosphatidylinositol 3-kinase, and MEK. After further validation of the technique, we identified several phosphorylation sites that were inhibited by these compounds but whose intensities did not always correlate with growth inhibition sensitivity. In contrast, several hundred phosphorylation sites that correlated with sensitivity/resistance were not in general inhibited by the compounds. These results indicate that markers of pathway activity may not always be reliable indicators of sensitivity of cancer cells to inhibitors that target such pathways, because the activity of parallel kinases can contribute to resistance. By mining our data we identified protein kinase C isoforms as one of such parallel pathways being more active in resistant cells. Consistent with the view that several parallel kinase pathways were contributing to resistance, inhibitors that target protein kinase C, MEK, and Janus kinase potentiated each other in arresting the proliferation of multidrug-resistant cells. Untargeted/unbiased approaches, such as the one described here, to quantify the activity of the intended target kinase pathway in concert with the activities of parallel kinase pathways will be invaluable to personalize therapies based on kinase inhibitors.
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PMID:Phosphoproteomic analysis of leukemia cells under basal and drug-treated conditions identifies markers of kinase pathway activation and mechanisms of resistance. 2254 87

ErbB3 receptors are unique members of the erbB receptor tyrosine kinases (RTKs), which are often aberrantly expressed and/or activated in human cancers. Unlike other members in the family, erbB3 lacks or has impaired kinase activity. To transduce cell signaling, erbB3 has to interact with other RTKs and to be phosphorylated by its interactive partners, of those, erbB2 is the most important one. ErbB3 is frequently co-expressed with other RTKs in cancer cells to activate oncogenic signaling, such as phosphoinositide-3-kinase/protein kinase B (Akt) pathway, mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway, Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway, etc. and thereby promote tumorigenesis. Numerous studies have demonstrated that activation of erbB3 signaling plays an important role in the progression of a variety of tumor types, such as erbB2-overexpressing breast cancer, castration-resistant prostate cancer, platinum refractory/resistant ovarian cancer, epidermal growth factor receptor TKI-resistant non-small-cell lung cancer, and others. Basic research on the underlying mechanisms implicated the functions of erbB3 as a major cause of treatment failure in cancer therapy. Thus, concomitant inhibition of erbB3 is thought to be required to overcome the resistance and to effectively treat human cancers. This review focuses on the latest advances in our understanding of erbB3-initiated signaling in the development of resistance to cancer treatments.
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PMID:Role of erbB3 receptors in cancer therapeutic resistance. 2444 84

Of the myeloproliferative neoplasms (MPNs), myelofibrosis (MF) is associated with the greatest symptom burden and poorest prognosis and is characterized by constitutional symptoms, cytopenias, splenomegaly and bone marrow fibrosis. A hallmark of MF is dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway that has led to the development of JAK inhibitors targeting this pathway. Calreticulin gene mutations have recently been identified in JAK2 mutation-negative patients with MF. Identification of JAK inhibitor resistance and broad contributions to MF disease pathogenesis from epigenetic deregulators, pathways that work in concert with JAK/STAT (that is, mammalian target of rapamycin/AKT/phosphoinositide 3-kinase, RAS/RAF/MEK, PIM kinase), fibrosis-promoting factors and the MF megakaryocyte, suggest that numerous options may be partnered with a JAK inhibitor. Therefore, we will discuss logical and potential partners for combination therapies for the treatment of patients with MF.
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PMID:Novel myelofibrosis treatment strategies: potential partners for combination therapies. 2488 74

Keratinocytes (KCs) play a critical role in maintaining the cutaneous structure and are involved in various physiological and pathologic processes of the skin. Many inflammatory skin diseases and skin cancers result from excessive proliferation and insufficient apoptosis of KCs. Recent data suggested that the sonic hedgehog (Shh) signalling pathway plays an essential role in the proliferation and apoptosis of normal KCs. However, the mechanism remains poorly defined. Here, we provide evidence that Shh signalling induces proliferation and inhibits apoptosis in normal KCs via cyclin D1 and Bcl2 in an extracellular signal-regulatedkinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent manner. In addition, the effect is independent of phosphoinositide-3 kinase (PI3K)/AKT or Janus kinase/signal transducer and activator of transcription (JAK/STAT) 1/3 pathways. Furthermore, we observed that epidermal growth factor receptor (EGFR) signalling modulates the activity of Shh signalling pathway; besides, Shh and EGFR signalling act additively to induce the ERK activation and the increases in cyclin D1 and Bcl2 thereby affecting proliferation and apoptosis in KCs in vitro. The present study suggests that the MEK/ERK1/2 activation is part of the mechanism of Shh signal-mediated proliferation and apoptosis in normal KCs. Our results may help to elucidate the regulatory mechanisms of the Shh pathway in normal KCs and the pathogenesis of related skin disorders.
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PMID:The MEK/ERK signalling cascade is required for sonic hedgehog signalling pathway-mediated enhancement of proliferation and inhibition of apoptosis in normal keratinocytes. 2525 90

Even though red blood cell (RBC) vesiculation is a well-documented phenomenon, notably in the context of RBC aging and blood transfusion, the exact signalling pathways and kinases involved in this process remain largely unknown. We have established a screening method for RBC vesicle shedding using the Ca(2+) ionophore ionomycin which is a rapid and efficient method to promote vesiculation. In order to identify novel pathways stimulating vesiculation in RBC, we screened two libraries: the Library of Pharmacologically Active Compounds (LOPAC) and the Selleckchem Kinase Inhibitor Library for their effects on RBC from healthy donors. We investigated compounds triggering vesiculation and compounds inhibiting vesiculation induced by ionomycin. We identified 12 LOPAC compounds, nine kinase inhibitors and one kinase activator which induced RBC shrinkage and vesiculation. Thus, we discovered several novel pathways involved in vesiculation including G protein-coupled receptor (GPCR) signalling, the phosphoinositide 3-kinase (PI3K)-Akt (protein kinase B) pathway, the Jak-STAT (Janus kinase-signal transducer and activator of transcription) pathway and the Raf-MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase) pathway. Moreover, we demonstrated a link between casein kinase 2 (CK2) and RBC shrinkage via regulation of the Gardos channel activity. In addition, our data showed that inhibition of several kinases with unknown functions in mature RBC, including Alk (anaplastic lymphoma kinase) kinase and vascular endothelial growth factor receptor 2 (VEGFR-2), induced RBC shrinkage and vesiculation.
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PMID:Identification of signalling cascades involved in red blood cell shrinkage and vesiculation. 2575 60

Dietary guidelines published in the past two decades have acknowledged the beneficial effects of myricetin, an important and common type of herbal flavonoid, against several human diseases such as inflammation, cardiovascular pathologies, and cancer. An increasing number of studies have shown the beneficial effects of myricetin against different types of cancer by modifying several cancer hallmarks including aberrant cell proliferation, signaling pathways, apoptosis, angiogenesis, and tumor metastasis. Most importantly, myricetin interacts with oncoproteins such as protein kinase B (PKB) (Akt), Fyn, MEK1, and JAK1-STAT3 (Janus kinase-signal transducer and activator of transcription 3), and it attenuates the neoplastic transformation of cancer cells. In addition, myricetin exerts antimitotic effects by targeting the overexpression of cyclin-dependent kinase 1 (CDK1) in liver cancer. Moreover, it also targets the mitochondria and promotes different kinds of cell death in various cancer cells. In the present paper, a critical review of the available literature is presented to identify the molecular targets underlying the anticancer effects of myricetin.
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PMID:Molecular mechanisms underlying anticancer effects of myricetin. 2645 50

The mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK1/2/ERK1/2) cascade is involved in the replication of several members of the Flaviviridae family, including hepatitis C virus and dengue virus. The effects of the cascade on the replication of classical swine fever virus (CSFV), a fatal pestivirus of pigs, remain unknown. In this study, MEK2 was identified as a novel binding partner of the E2 protein of CSFV using yeast two-hybrid screening. The E2-MEK2 interaction was confirmed by glutathione S-transferase pulldown, coimmunoprecipitation, and laser confocal microscopy assays. The C termini of E2 (amino acids [aa] 890 to 1053) and MEK2 (aa 266 to 400) were mapped to be crucial for the interaction. Overexpression of MEK2 significantly promoted the replication of CSFV, whereas knockdown of MEK2 by lentivirus-mediated small hairpin RNAs dramatically inhibited CSFV replication. In addition, CSFV infection induced a biphasic activation of ERK1/2, the downstream signaling molecules of MEK2. Furthermore, the replication of CSFV was markedly inhibited in PK-15 cells treated with U0126, a specific inhibitor for MEK1/2/ERK1/2, whereas MEK2 did not affect CSFV replication after blocking the interferon-induced Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway by ruxolitinib, a JAK-STAT-specific inhibitor. Taken together, our results indicate that MEK2 positively regulates the replication of CSFV through inhibiting the JAK-STAT signaling pathway. IMPORTANCE Mitogen-activated protein kinase kinase 2 (MEK2) is a kinase that operates immediately upstream of extracellular regulated kinase 1/2 (ERK1/2) and links to Raf and ERK via phosphorylation. Currently, little is known about the role of MEK2 in the replication of classical swine fever virus (CSFV), a devastating porcine pestivirus. Here, we investigated the roles of MEK2 and the MEK2/ERK1/2 cascade in the growth of CSFV for the first time. We show that MEK2 positively regulates CSFV replication. Notably, we demonstrate that MEK2 promotes CSFV replication through inhibiting the interferon-induced JAK-STAT signaling pathway, a key antiviral pathway involved in innate immunity. Our work reveals a novel role of MEK2 in CSFV infection and sheds light on the molecular basis by which pestiviruses interact with the host cell.
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PMID:Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway. 2913 31

Vascular leakage is a hallmark of the inflammatory response. Acute changes in endothelial permeability are due to posttranslational changes in intercellular adhesion and cytoskeleton proteins. However, little is known about the mechanisms leading to long-term changes in vascular permeability. Here, we show that interleukin-6 (IL-6) promotes an increase in endothelial monolayer permeability that lasts over 24 h and demonstrate that activation of Src and MEK/ERK pathways is required only for short-term increases in permeability, being dispensable after 2 h. In contrast, Janus kinase (JAK)-mediated STAT3 phosphorylation at Y705 (but not S727) and de novo synthesis of RNA and proteins are required for the sustained permeability increases. Loss of junctional localization of VE-cadherin and ZO-1 is evident several hours after the maximal IL-6 response, thus suggesting that these events are a consequence of IL-6 signaling, but not a cause of the increased permeability. Understanding the mechanisms involved in sustaining vascular permeability may prove crucial to allow us to directly target vascular leakage and minimize tissue damage, thus reducing the rates of mortality and chronic sequelae of excessive edema. Targeting endothelial-specific mechanisms regulating barrier function could provide a new therapeutic strategy to prevent vascular leakage while maintaining the immune response and other beneficial aspects of the inflammatory response that are required for bacterial clearance and tissue repair.
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PMID:Interleukin-6 promotes a sustained loss of endothelial barrier function via Janus kinase-mediated STAT3 phosphorylation and de novo protein synthesis. 2935 6

Pancreatic stem/progenitor cells convert from a proliferative to a differentiated fate passing through proliferation cease to a resting state. However, the molecular mechanisms of cell cycle arrest are poorly understood. In this study, we demonstrated that the microRNA-124a (miR-124a) inhibited the proliferation of pancreatic progenitor cells both in vitro and ex vivo and promoted a quiescent state. The miR-124a directly targeted SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1), IQ motif-containing GTPase-activating protein 1 (IQGAP1), signal transducer and activator of transcription 3 (STAT3), and cyclin D2 (CCND2), thereby inactivating epidermal growth factor receptor (EGFR) downstream signaling pathways including mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK), phosphatidylinositol 3-kinase-protein kinase B (PI3K/AKT) and Janus kinase (JAK)/STAT3. miR-124a blocked cell proliferation mainly through targeting STAT3 to inhibit PI3K/AKT and JAK/STAT3 signaling. Moreover, miR-124a expression was negatively regulated by EGFR downstream PI3K/AKT signaling. These results indicated that miR-124a and EGFR signaling mutually interact to form a regulating circuit that determines the proliferation of pancreatic progenitor cells.
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PMID:Mutual inhibitions between epidermal growth factor receptor signaling and miR-124a control pancreatic progenitor proliferation. 3053 82


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