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

---

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

The B cell antigen receptor (BCR) activates Ras, a GTPase that promotes cell proliferation by activating the Raf-1/MEK/ERK signaling module and other signaling enzymes. In its active GTP-bound form, the Rap1 GTPase may act as a negative regulator of Ras-mediated signaling by sequestering Ras effectors (e.g., Raf-1) and preventing their activation. In this report, we show that BCR engagement activates Rap1 and that this is dependent on production of diacylglycerol (DAG) by phospholipase C-gamma. Activation of Rap1 by the BCR was greatly reduced in phospholipase C-gamma-deficient B cells, whereas both a synthetic DAG and phorbol dibutyrate could activate Rap1 in B cells. We had previously shown that C3G, an activator of Rap1, associates with the Crk adaptor proteins in B cells and that BCR engagement causes Crk to bind to the Cas and Cbl docking proteins. However, the DAG-dependent pathway by which the BCR activates Rap1 apparently does not involve Crk signaling complexes since phorbol dibutyrate could activate Rap1 without inducing the formation of these complexes. Thus, the BCR activates Rap1 via a novel DAG-dependent pathway.
...
PMID:Activation of the Rap1 GTPase by the B cell antigen receptor. 978 33

The mitogen-activated protein kinase (MAPK) pathway, classically associated with cell growth and dependent on tyrosine kinases such as MAPK kinase (MEK), can modulate smooth muscle contractility, and our laboratory has tested the hypothesis that 5-HT can activate the MAPK pathway in arterial smooth muscle through activation of a 5-HT2A receptor. Tyrosine kinase inhibitors including genistein and the specific MEK inhibitor PD098059, but not the inactive tyrosine kinase congener daidzein reduced and shifted 5-HT-induced contraction rightward in isolated, endothelium-denuded rat arteries. Activation of a tyrosine kinase/MEK via the 5-HT2A receptor was partially independent of two major signaling pathways typically associated with the 5-HT2A receptor--activation of L-type voltage gated calcium channels and phospholipase C. Western analyses using antibodies directed against tyrosyl-phosphorylated-, activated Erk MAPK, and MEK proteins from cultured aortic smooth muscle cells demonstrated that 5-HT activated MEK and the Erk MAPKs in a time-, concentration-, receptor- and tyrosine kinase-dependent manner. Taken together, these findings provide evidence for a novel pathway of vascular signal transduction--activation of the MAPK pathway--for the 5-HT2A receptor.
...
PMID:Activation of the mitogen-activated protein kinase pathway via the 5-HT2A receptor. 992 53

In the present study, we investigated the involvement of Ca2+-signaling and protein kinases in the effect of Ca2+-ATPase inhibitors on the activation of cytosolic phospholipase A2 (cPLA2) in human polymorphonuclear neutrophils. We found that activity and mobility on electrophoresis gels of the cPLA2 protein were significantly increased by f-Met-Leu-Phe (fMLP), 12-myristate 13-acetate (PMA) and the Ca2+-ATPase inhibitors, thapsigargin and cyclopiazonic acid. This effect was completely suppressed by staurosporine. Calphostin C partially inhibited the fMLP- and PMA-induced cPLA 2 activation, but had no influence on thapsigargin- and cyclopiazonic acid-treated cells. Thapsigargin and cyclopiazonic acid also showed no effect on protein kinase C activity. However, the thapsigargin- and cyclopiazonic acid-induced cPLA2 activation was completely inhibited by the tyrosine kinase inhibitor, erbstatin, and Ca2+ chelator, EGTA. In addition, the cPLA2 activity was reduced after pretreatment with the mitogen-activated protein kinase kinase inhibitor PD98059. The arachidonic acid release was significantly reduced in cells pretreated with the cPLA2 inhibitor, AACOCF3. Furthermore, we found that the human neutrophil cPLA2 cDNA contain a Ca2+-dependent-lipid binding domain which shares homology to several other enzymes such as protein kinase C and phospholipase C. Our results suggest that tyrosine kinases and the MAP kinase cascade are involved in Ca2+-ATPase inhibitor-induced activation and phosphorylation of cPLA2. Protein kinase C is not required in this event.
...
PMID:Role of Ca2+-ATPase inhibitors in activation of cytosolic phospholipase A2 in human polymorphonuclear neutrophils. 993 28

Mitogen-activated protein kinase (MAPK) cascades underlie long-term mitogenic, morphogenic, and secretory activities of purinergic receptors. In HEK-293 cells, N-ethylcarboxamidoadenosine (NECA) activates endogenous A2BARs that signal through Gs and Gq/11. UTP activates P2Y2 receptors and signals only through Gq/11. The MAPK isoforms, extracellular-signal regulated kinase 1/2 (ERK), are activated by NECA and UTP. H-89 blocks ERK activation by forskolin, but weakly affects the response to NECA or UTP. ERK activation by NECA or UTP is unaffected by a tyrosine kinase inhibitor (genistein), attenuated by a phospholipase C inhibitor (U73122), and is abolished by a MEK inhibitor (PD098059) or dominant negative Ras. Inhibition of protein kinase C (PKC) by GF 109203X failed to block ERK activation by NECA or UTP, however, another PKC inhibitor, Ro 31-8220, which unlike GF 109203X, can block the zeta-isoform, and prevents UTP- but not NECA-induced ERK activation. In the presence of forskolin, Ro 31-8220 loses its ability to block UTP-stimulated ERK activation. PKA has opposing effects on B-Raf and c-Raf-1, both of which are found in HEK-293 cells. The data are explained by a model in which ERK activity is modulated by differential effects of PKC zeta and PKA on Raf isoforms.
...
PMID:A2B adenosine and P2Y2 receptors stimulate mitogen-activated protein kinase in human embryonic kidney-293 cells. cross-talk between cyclic AMP and protein kinase c pathways. 1002 23

This study uses human alveolar macrophages to determine whether activation of a phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) is linked to activation of the p42/44 (ERK) kinases by LPS. LPS-induced ERK kinase activation was inhibited by tricyclodecan-9-yl xanthogenate (D609), a relatively specific inhibitor of PC-PLC. LPS also increased amounts of diacylglycerol (DAG), and this increase in DAG was inhibited by D609. LPS induction of DAG was, at least in part, derived from PC hydrolysis. Ceramide was also increased in LPS-treated alveolar macrophages, and this increase in ceramide was inhibited by D609. Addition of exogenous C2 ceramide or bacterial-derived sphingomyelinase to alveolar macrophages increased ERK kinase activity. LPS also activated PKC zeta, and this activation was inhibited by D609. LPS-activated PKC zeta phosphorylated MAP kinase kinase, the kinase directly upstream of the ERK kinases. LPS-induced cytokine production (RNA and protein) was also inhibited by D609. As an aggregate, these studies support the hypothesis that one way by which LPS activates the ERK kinases is via activation of PC-PLC and that activation of a PC-PLC is an important component of macrophage activation by LPS.
...
PMID:A phosphatidylcholine-specific phospholipase C regulates activation of p42/44 mitogen-activated protein kinases in lipopolysaccharide-stimulated human alveolar macrophages. 1007 52

CRF exerts a key neuroregulatory control on the function of the hypothalamic-pituitary-adrenal axis. These effects are thought to be mediated primarily through activation of Gs-coupled plasma membrane receptors. In the present study, we investigated the effects of activation of CRF receptors by sauvagine on signaling pathways that converge on phosphorylation of the transcription factor calcium/cAMP response element-binding protein (CREB). Studies were undertaken using CHO cell lines transfected with either rat CRF-1 or CRF-2alpha receptors. Signaling pathways were investigated using immunocytochemical, Western blot, and imaging techniques. Treatment with sauvagine increased phosphorylation of p42/p44, but not of p38 or stress-activated protein kinase (SAPK)/JUN N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases correlating with increased p42/p44 MAP kinase activity. Mobilization of intracellular Ca2+ stores was observed in cells treated with high concentrations (100 nM, 1 microM) of sauvagine. A time- and dose-dependent increase in phosphorylation of the transcription factor CREB was observed in cultures treated with sauvagine. Phosphorylation of CREB occurred at lower concentrations of sauvagine than those required to mobilize intracellular calcium stores, and phosphorylation was not blocked by the mitogen-activated protein kinase kinase inhibitor PD98059 at a concentration (1 microM) that fully inhibited phosphorylation of MAP kinase. Cotreatment of cultures with the protein kinase A inhibitor H89 (10 microM) blocked fully the stimulatory actions of sauvagine (0.1 nM, 1 nM) on phosphorylation of CREB, but not those on phosphorylation of MAP kinase. Phosphorylation of MAP kinase was partially blocked by the phosphoinositide 3-kinase inhibitor LY294002 (5 microM) and by the phosphoinositide-phospholipase C inhibitor U73122 (10 microM). These data demonstrate that cAMP-, Ca2+-, and MAP kinase-dependent signaling pathways are activated by stimulation of CRF-1 and CRF-2alpha receptors. However, in these cells, only protein kinase A-dependent pathways contribute significantly to enhanced phosphorylation of CREB. These represent the first reported observations of CRF receptor-mediated phosphorylation of the transcription factor CREB and activation of MAP kinase signal transduction pathways.
...
PMID:Corticotropin-releasing factor type 1 and type 2alpha receptors regulate phosphorylation of calcium/cyclic adenosine 3',5'-monophosphate response element-binding protein and activation of p42/p44 mitogen-activated protein kinase. 1009 84

The endogenous nucleoside adenosine is thought to play a role in the pathophysiology of asthma by stimulating mast cells. We previously showed that the human mast cell line HMC-1 expresses A2A and A2B receptors, and that both receptors activate adenylate cyclase via Gs-protein but that only A2B receptors are also coupled to phospholipase C via Gq proteins. Stimulation of A2B but not A2A receptors induced production of interleukin-8 (IL-8) from HMC-1 cells. The mechanism by which adenosine promotes IL-8 synthesis has not been defined. In this study, we tested the hypothesis that mitogen-activated protein kinase (MAPK) signaling pathways are involved in this process. Stimulation of HMC-1 with the stable adenosine analog NECA (5'-N-ethylcarboxamidoadenosine) activated p21(ras) and both p42 and p44 isoforms of extracellular signal-regulated kinase (ERK). NECA (10 microM) induced a 1.9 +/- 0. 06-fold increase in ERK activity, whereas 10 microM of the selective A2A agonist CGS 21680 (4-((N-ethyl-5'-carbamoyladenos-2-yl)-aminoethyl)-phenylpropionic acid) had no effect. NECA, in parallel with the activation of ERK, also stimulated the p46 isoform of c-Jun N-terminal kinase (MEK) and p38 MAPK. Furthermore, the selective MAPK/ERK kinase 1 inhibitor PD 98059 (2'-amino-3'-methoxyflavone), and p38 MAPK inhibitors SB 202190 (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole) and SB 203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H- imidaz ole) blocked A2B receptor-mediated production of IL-8. These results indicate that extracellular adenosine can regulate ERK, c-Jun N-terminal kinase, and p38 MAPK signaling cascades and that activation of ERK and p38 MAPK pathways are essential steps in adenosine A2B receptor-dependent stimulation of IL-8 production in HMC-1.
...
PMID:Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. 1010 Oct 31

Nerve growth factor differentiates precursor cells into sympathetic neurons. Does acquisition of a "neuronal" phenotype after nerve growth factor involve biosynthesis of chromogranin A, the major soluble protein in chromaffin granule cores? Nerve growth factor activated chromogranin A gene expression 7.6-fold in PC12 pheochromocytoma cells, and similarly activated PC12-transfected mouse, rat or human chromogranin A promoter/reporter constructs. Chromogranin A promoter 5'-deletions narrowed the nerve growth factor response element to a region from - 77 to - 61 bp upstream of the cap site, a region containing the chromogranin A cyclic AMP response element (TGACGTAA). Three different site-directed mutations of the cyclic AMP response element each reduced the nerve growth factor effect by >90%. Transfer of the cyclic AMP response element to a heterologous (thymidine kinase) promoter activated that promoter approximately 5-fold after nerve growth factor, while transfer of a cyclic AMP response element point-gap mutant (TGA-GTAA) to a heterologous promoter abolished the nerve growth factor effect. These findings indicate that the cyclic AMP response element in cis is, at least in part, both necessary and sufficient to activate the chromogranin A gene. Chemical blockade of the nerve growth factor receptor TrkA or the mitogen-activated protein kinase pathway component MEK substantially diminished nerve growth factor-induced expression of chromogranin A. By contrast, the response of chromogranin A to nerve growth factor was not impaired after blockade of phospholipase C-gamma or phosphoinositide-3 kinase. Chemical blockade of TrkA, Ras, MEK or mitogen-activated protein kinase similarly inhibited nerve growth factor activation of chromogranin A. Expression of constitutively activated Ras, Raf or MEK mutants increased chromogranin A promoter activity. Expression of dominant negative (inhibitory) mutants of Sos, Ha-Ras, Rafl, mitogen-activated protein kinase, ribosomal protein S6 serine kinase II (CREB kinase) or CREB (KCREB) each inhibited the nerve growth factor-induced increase in chromogranin A promoter activity. Thus, each component of the mitogen-activated protein kinase pathway is crucially involved in relaying the nerve growth factor signal in trans to the chromogranin A gene, in the following proposed sequence: nerve growth factor --> TrkA --> Shc/Grb2/Sos --> Ras --> Raf --> MEK --> mitogen-activated protein kinase --> ribosomal protein S6 serine kinase II --> CREB cyclic AMP response element.
...
PMID:Neurotrophin activation of catecholamine storage vesicle protein gene expression: signaling to chromogranin a biosynthesis. 1019 63

We have examined fibroblast growth factor (FGF) receptor-1 mediated signal transduction in differentiation of endothelial cells (EC). The activated FGFR-1 couples to Ras through two adaptor proteins, FRS2 and Shc. In FGF-2 treated proliferating EC, FRS2 as well as Shc are tyrosine phosphorylated and interact with Grb2. In contrast, in FGF-2 treated differentiating cells, Shc, but not FRS2, is engaged in Grb2-interactions. Sustained MAP kinase activity has previously been implicated in differentiation. In FGF stimulated proliferating and differentiating endothelial cells, the MAP kinase Erk2 is activated in a sustained manner. Inhibition of MEK and MAP kinase activity by PD98059 treatment of cells, still allows EC tube formation. The FGFR-1 mediates activation of protein kinase C (PKC) through direct binding and activation of phospholipase C-gamma (PLC-gamma), and has also been shown to activate the cytoplasmic tyrosine kinase Src. Treatment of the cells with the PKC inhibitor bisindolylmaleimide does not prevent tube formation. In contrast, Src kinase activity is a prerequisite for EC differentiation, since treatment of the cells with PP1, a Src family specific inhibitor, abrogates tube formation. In differentiating EC, FGF-2 induces complex formation between Src and focal adhesion kinase (FAK). These data indicate that the Ras pathway is initiated via Shc or FRS2, dependent on the cellular program. Blocking the function of Src family kinases, attenuates differentiation.
...
PMID:Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation. 1036 56

Gastrin-releasing peptide (GRP) and its amphibian homolog, bombesin, are potent secretogogues in mammals. We determined the roles of intracellular free Ca(2+) ([Ca(2+)](i)), protein kinase C (PKC), and mitogen-activated protein kinases (MAPK) in GRP receptor (GRP-R)-regulated secretion. Bombesin induced either [Ca(2+)](i) oscillations or a biphasic elevation in [Ca(2+)](i). The biphasic response was associated with peptide secretion. Receptor-activated secretion was blocked by removal of extracellular Ca(2+), by chelation of [Ca(2+)](i), and by treatment with inhibitors of phospholipase C, conventional PKC isozymes, and MAPK kinase (MEK). Agonist-induced increases in [Ca(2+)](i) were also inhibited by dominant negative MEK-1 and the MEK inhibitor, PD89059, but not by an inhibitor of PKC. Direct activation of PKC by a phorbol ester activated MAPK and stimulated peptide secretion without a concomitant increase in [Ca(2+)](i). Inhibition of MEK blocked both bombesin- and phorbol 12-myristate 13-acetate-induced secretion. GRP-R-regulated secretion is initiated by an increase in [Ca(2+)](i); however, elevated [Ca(2+)](i) is insufficient to stimulate secretion in the absence of activation of PKC and the downstream MEK/MAPK pathways. We demonstrated that the activity of MEK is important for maintaining elevated [Ca(2+)](i) levels induced by GRP-R activation, suggesting that MEK may affect receptor-regulated secretion by modulating the activity of Ca(2+)-sensitive PKC.
...
PMID:Multiple protein kinase pathways are involved in gastrin-releasing peptide receptor-regulated secretion. 1044 56


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---