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)

Intermediate filament proteins have been isolated from ME-180, cells of a human cervical carcinoma. Eight of these proteins have been identified as keratins by immunologic cross-reactivity to antibodies raised against authentic human epidermal keratins. The ME-180 keratin proteins consist of two major subunits designated MEK-1 and MEK-2 with approximate molecular weights of 58,000 and 53,000, respectively, and six minor subunits of 59, 57, 52.5, 50.5, 45, and 40 kilodaltons. When ME-180 cells were incubated for 2-24 h in the presence of [32P]orthophosphate, MEK-1 and MEK-2 as well as the 52.5- and 40-kilodalton keratins were phosphorylated at their serine residues. V8 protease digests revealed that phosphorylation of MEK-2 is restricted to one peptide representing approximately half the molecule. Regulation of MEK-1 and MEK-2 phosphorylation has been studied by prelabeling the cells for 2 h in 32P-labeled medium. This was followed by up to 2 h of continued incubation in the same medium after the addition of a variety of perturbing agents. The phosphorylation of MEK-2 increased in the presence of 10(-4) M dibutyryl cyclic AMP (twofold), 1 mM methylisobutylxanthine (2.5-fold), 10(-5) M isoproterenol (fivefold), and 10(-9) M cholera toxin (sevenfold). In contrast, MEK-1 phosphorylation was unaffected by these agents. Neither cyclic GMP, Ca++, hydrocortisone, nor epidermal growth factor had any effect on the phosphorylation of MEK-1 or MEK-2. The results indicate that the phosphorylation of these two keratins is independently controlled by cyclic AMP-dependent kinase for MEK-2 and by cyclic nucleotide-independent kinase for MEK-1. The observed differences in control suggest distinct functions for MEK-1 and MEK-2 within the cytoskeletal network.
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PMID:Dual regulation of intermediate filament phosphorylation. 619 63

Atrial natriuretic peptide (ANP) has been shown to inhibit the proliferation of various types of cells including glomerular mesangial cells. The activation of mitogen-activated protein kinase (MAPK) is one of the main signal transduction systems leading to cell proliferation. MAPK is tightly regulated by the activating kinase, MEK, and specific phosphatase MKP-1. Constitutive expression of MKP-1 has been shown to inhibit cell proliferation by suppressing MAPK activity. In order to understand the mechanism of the anti-proliferative effect of ANP, we examined whether ANP could inhibit MAPK by inducing MKP-1 in cultured rat glomerular mesangial cells. ANP increased the expression of MKP-1 mRNA in a dose-dependent (10 nM maximum) and time-dependent, with a peak stimulation at 30 min, manner. Receptor for ANP is a transmembrane guanylyl cyclase. Activation of guanylyl cyclase of ANP receptor by ligand plays an essential role in ANP signal transduction. 8-Bromo-cGMP, a cell permeable analogue of cyclic GMP, and sodium nitroprusside, an activator of soluble guanylyl cyclase, could mimic the effects of ANP and were able to induce the expression of MKP-1 in a similar time course as ANP. The protein expression of MKP-1 was maximally stimulated by ANP at 120 min. Treatment of the cells with ANP for 120 min resulted in an inhibition of phorbol ester-induced activation of MAPK, while the activation of MEK was not affected by ANP. These results indicate that ANP might inhibit the proliferation of mesangial cells by inactivating MAPK through the induction of MKP-1.
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PMID:Atrial natriuretic peptide induces the expression of MKP-1, a mitogen-activated protein kinase phosphatase, in glomerular mesangial cells. 855 Jun 16

1. Whole-cell patch-clamp recording techniques were used to investigate the G protein subtype and related signalling molecules involved in activation of a nonspecific cation (NSC) current in rat cultured retinal pigment epithelial (RPE) cells. 2. Under control conditions, in 130 mM NaCl with K+ aspartate in the pipette, cytosolic dialysis with guanosine-5'-O-(3-triphosphate) (GTPgammaS, 0.1 mM) activated a large non-inactivating NSC current in 80% of the cells recorded from. 3. Loading RPE cells with antibodies (10 microg-ml(-1)) against the alpha subunit of all PTX-sensitive G proteins (G(alpha i/o/t/z)) reduced NSC current activation to 11%, while loading RPE cells with antibodies directed specifically against the alpha subunits of the Gi subclass (G(alpha i-3)) completely abolished current activation. In RPE cells loaded with anti-G(alpha s) activation of the NSC current was unaffected. 4. Investigation of the potential downstream mediators in the G(alpha i) NSC channel pathway revealed that activation of the cation conductance was unaffected by treatment of RPE cells with the selective protein kinase C inhibitor GF 109203X (3 microM) or the selective CaM kinase II inhibitor KN-93 (50 microM). However, NSC current activation was delayed and the current amplitude reduced in the presence of the nonselective kinase inhibitor H-7 (100 microM) or the selective inhibitor of MAPKK (MEK) activation, PD 98059 (50 microM). 5. In the absence of GTPgammaS, the NSC current was not activated by superfusion of the cells with the cyclic GMP kinase activator dibutyryl-cyclic GMP or with the adenylate cyclase activator forskolin. 6. These results support the involvement of a G protein of the G(alpha i) subclass in the activation of a NSC current in rat RPE cells, and suggest a potential modulatory role for MAP kinase-dependent phosphorylation in current regulation.
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PMID:Activation of a nonspecific cation current in rat cultured retinal pigment epithelial cells: involvement of a G(alpha i) subunit protein and the mitogen-activated protein kinase signalling pathway. 972 Jul 81

This study examined the signal transduction pathway(s) leading to phosphorylation of p38 in human neutrophils stimulated with lipopolysaccharide and formyl peptides. Blockade of the nitric oxide (NO) pathway in neutrophils with the NO synthase inhibitor N-nitro-L-arginine methyl ester or by treatment with the NO scavenger 2-phenyl-tetramethylimidazoline-1-oxyl-3-oxide attenuated phosphorylation of the mitogen-activated protein kinase p38 in response to lipopolysaccharide but not fMet-Leu-Phe. Using the NO releasing agents S-nitroso-N-acetylpenicillamine and sodium nitroprusside it was determined that nitric oxide is sufficient to cause an increase in phosphorylation of p38. Increasing cellular cGMP with phosphodiesterase inhibitors, by stimulation of soluble guanylyl cyclase with YC-1 or with exogenous dibutyryl cGMP resulted in mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 3,6 (MEK3,6) activation and phosphorylation of p38. This phenomenon was specific for MEK3,6, because these agents had no effect on the phosphorylation state of MEK1,2. A role for protein kinase G but not protein kinase A downstream of lipopolysaccharide but not formylmethionylleucylphenylalanine was shown using the specific inhibitors KT5823 and H89, respectively. These data indicate that activation of p38 by fMet-Leu-Phe and lipopolysaccharide involve different mechanisms, and that activation of protein kinase G by NO-dependent stimulation of guanylyl cyclase is necessary and sufficient for phosphorylation of p38 downstream of lipopolysaccharide.
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PMID:Activation of p38 mitogen-activated protein kinase by lipopolysaccharide in human neutrophils requires nitric oxide-dependent cGMP accumulation. 986 77

The effects of mitogen-activated protein (MAP) kinase inhibitors or phosphodiesterase (PDE) inhibitors on interleukin (IL)-1-induced cytokines production in synovium-derived cells were investigated. Human synoviocyte (HS) or synovial sarcoma (SW982) stimulated by IL-1beta (100 ng/ml) produced various cytokines including IL-6, IL-8, GROalpha, VEGF, basic FGF and tumor necrosis factor alpha (TNFalpha) in vitro. SB202190 or SB203580, an inhibitor of p38 MAP kinase, inhibited all cytokines production in both cells. PD98059, an inhibitor of MAP kinase kinase (MEK), inhibited IL-6, IL-8 and basic FGF production in HS and all cytokines production except basic FGF in SW982. However, many of its effects were weaker than those of SB202190 or SB203580. Quazinone, an inhibitor of cyclic GMP-inhibited PDE, scarcely affected cytokines production in both cells. Rolipram or R0201724, an inhibitor of cyclic AMP-specific PDE, inhibited IL-8 and basic FGF production in HS and TNFalpha production in SW982, however, it enhanced the other cytokines production in SW982. These results suggest that the activation of MAP kinase cascade may be important for IL-1-induced cytokines production in synovium-derived cells. On the other hand, the role of cyclic AMP may be dependent on cell and cytokine types.
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PMID:Effects of mitogen-activated protein kinase inhibitors or phosphodiesterase inhibitors on interleukin-1-induced cytokines production in synovium-derived cells. 1042 32

Several of the hepatic microsomal cytochromes P-450 (CYP) including CYP3A are inducible by phenobarbital (PB). However, the intracellular pathways involved in the action of PB on CYP3A remain poorly known. With the aim to unravel some of the main aspects of PB signaling, we first devised a simple model of mouse cultured primary hepatocytes in which CYP3A mRNA and protein were strongly induced by PB in the absence of dexamethasone and were at maximum levels after a 48-h treatment with a 2-mM dose of PB. Under these culture conditions, we studied the effects of inhibitors and activators of different protein kinases or phosphatases on CYP3A mRNA and protein induction by PB. CYP3A-induced expression was inhibited by activators of cyclic AMP-dependent protein kinase (PKA) (dibutyryl-cyclic AMP and forskolin) whereas inhibition of PKA by PKA inhibitor enhanced induction. 8-br-cGMP produced effects similar to the activators of PKA, and so did the specific inhibitor of cGMP-dependent protein kinase, beta-phenyl-1, N(2)-etheno-8-bromoguanosine-3,5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-PET-cGMPS). Inhibition of Ca(2+)/calmodulin-dependent protein kinase by KN-62 or the intracellular Ca(2+) chelator BAPTA-AM produced an inhibition of CYP3A induction by PB. Specific inhibitors of protein kinase C, mitogen-activated protein kinase kinase, phosphatidylinositol-3-kinase, or serine/threonine phosphatase did not produce any effect. Taken together, our results suggest that CYP3A induction by PB is regulated positively by calmodulin-dependent protein kinase and cGMP-dependent protein kinase, and negatively by PKA in mouse hepatocytes in primary culture.
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PMID:Involvement of cyclic nucleotide- and calcium-regulated pathways in phenobarbital-induced cytochrome P-450 3A expression in mouse primary hepatocytes. 1045 3

Phosphorylation of cyclic AMP response element binding protein (CREB) at amino acid serine 133 appears as an important link between the norepinephrine (NE)-induced activation of second messenger systems and the stimulation of melatonin biosynthesis. Here we investigated in the rat pineal gland: 1) the type of protein kinase that mediates CREB phosphorylation: and 2) its impact on melatonin biosynthesis. Immunochemical or immunocytochemical demonstration of serine133-phosphorylated cyclic AMP regulated element binding protein (pCREB) and radioimmunological detection of melatonin revealed that only cyclic AMP-dependent protein kinase (PKA) inhibitors suppressed NE-induced CREB phosphorylation and stimulation of melatonin biosynthesis, whereas inhibitors of cyclic GMP-dependent protein kinase (PKG), mitogen-activated protein kinase kinase, protein kinase C, or calcium-calmodulin-dependent protein kinase (CaMK) were ineffective. Investigations with cyclic AMP-agonist pairs that selectively activate either PKA type I or II link NE-induced CREB phosphorylation and stimulation of melatonin biosynthesis to the activation of PKA type II. Our data suggest that PKA type II plays an important role in the transcriptional control of melatonin biosynthesis in the rat pineal organ.
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PMID:CREB phosphorylation and melatonin biosynthesis in the rat pineal gland: involvement of cyclic AMP dependent protein kinase type II. 1053 67

Vascular smooth muscle cells (VSMC) exist in either a contractile or a synthetic phenotype in vitro and in vivo. The molecular mechanisms regulating phenotypic modulation are unknown. Previous studies have suggested that the serine/threonine protein kinase mediator of nitric oxide (NO) and cyclic GMP (cGMP) signaling, the cGMP-dependent protein kinase (PKG) promotes modulation to the contractile phenotype in cultured rat aortic smooth muscle cells (RASMC). Because of the potential importance of the mitogen-activated protein kinase (MAP kinase) pathways in VSMC proliferation and phenotypic modulation, the effects of PKG expression in PKG-deficient and PKG-expressing adult RASMC on MAP kinases were examined. In PKG-expressing adult RASMC, 8-para-chlorophenylthio-cGMP activated extracellular signal- regulated kinases (ERK1/2) and c-Jun N-terminal kinase (JNK). The major effect of PKG activation was increased activation by MAP kinase kinase (MEK). The cAMP analog, 8-Br-cAMP inhibited ERK1/2 activation in PKG-deficient and PKG-expressing RASMC but had no effect on JNK activity. The effects of PKG on ERK and JNK activity were additive with those of platelet-derived growth factor (PDGF), suggesting that PKG activates MEK through a pathway not used by PDGF. The stimulatory effects of cGMP on ERK and JNK activation were also observed in low-passaged, contractile RASMC still expressing endogenous PKG, suggesting that the effects of PKG expression were not artifacts of cell transfections. These results suggest that in contractile adult RASMC, NO-cGMP signaling increases MAP kinase activity. Increased activation of these MAP kinase pathways may be one mechanism by which cGMP and PKG activation mediate c-fos induction and increased proliferation of contractile adult RASMC.
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PMID:Activation of mitogen-activated protein kinase pathways by cyclic GMP and cyclic GMP-dependent protein kinase in contractile vascular smooth muscle cells. 1056 6

Nitric oxide (NO) reduces the severity of pulmonary vascular disease in rats as do elastase inhibitors. We therefore hypothesized that NO inhibits elastase by suppressing mitogen-activated protein kinases that trans-activate AML1B, a transcription factor for elastase. We used cultured pulmonary artery smooth muscle cells in which serum-treated elastin (STE) induces a > threefold increase in elastase activity as evaluated by solubilization of [(3)H]-elastin. NO donors (SNAP and DETA NONOate) inhibited elastase in a dose-dependent manner as did a cGMP mimetic (8-pCPT-cGMP). SNAP inhibition of elastase was reversed by coadministration of a cGMP-PKG inhibitor (Rp-8-pCPT-cGMP). The STE-induced increase in phospho-ERK was suppressed by NO donors and the cGMP mimetic, and reversed by cGMP-PKG inhibitor, as was expression of AML1B and DNA binding in nuclear extracts. A concomitant increase in p38 phosphorylation was also inhibited by SNAP, but whereas MEK inhibitor (PD98059) suppressed elastase and AML1B-DNA binding, a p38 inhibitor (SB202190) did not. Our study uniquely links NO with inhibition of elastase-dependent matrix remodeling in vascular disease by suggesting a cGMP-PKG-related mechanism suppressing ERK-mediated partitioning of AML1B in nuclear extracts.
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PMID:Nitric oxide reduces vascular smooth muscle cell elastase activity through cGMP-mediated suppression of ERK phosphorylation and AML1B nuclear partitioning. 1074 37

The bioactivity of endothelium-derived nitric oxide (NO) reflects its rates of production and of inactivation by superoxide (O(2)(*-)), a reactive species dismutated by extracellular superoxide dismutase (ecSOD). We have now examined the complementary hypothesis, namely that NO modulates ecSOD expression. The NO donor DETA-NO increased ecSOD expression in a time- and dose-dependent manner in human aortic smooth muscle cells. This effect was prevented by the guanylate cyclase inhibitor ODQ and by the protein kinase G (PKG) inhibitor Rp-8-CPT-cGMP. Expression of ecSOD was also increased by 8-bromo-cGMP, but not by 8-bromo-cAMP. Interestingly, the effect of NO on ecSOD expression was prevented by inhibition of the MAP kinase p38 but not of the MAP kinase kinase p42/44, suggesting that NO modulates ecSOD expression via cGMP/PKG and p38MAP kinase-dependent pathways, but not through p42/44MAP kinase. In aortas from mice lacking the endothelial nitric oxide synthase (eNOS), ecSOD was reduced more than twofold compared to controls. Treadmill exercise training increased eNOS and ecSOD expression in wild-type mice but had no effect on ecSOD expression in mice lacking eNOS, suggesting that this effect of exercise is meditated by endothelium-derived NO. Upregulation of ecSOD expression by NO may represent an important feed-forward mechanism whereby endothelial NO stimulates ecSOD expression in adjacent smooth muscle cells, thus preventing O(2)(*-)-mediated degradation of NO as it traverses between the two cell types.
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PMID:Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. 1084 22


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