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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aggregating Dictyostelium cells secrete cAMP during cell aggregation. cAMP induces two fast responses, the production of more cAMP (relay) and directed cell locomotion (chemotaxis). Extracellular cAMP binds to G-protein-coupled receptors leading to the activation of second messenger pathways, including the activation of adenylyl cyclase, guanylyl cyclase, phospholipase C and the opening of plasma membrane Ca2+ channels. Many genes encoding these sensory transduction proteins have been cloned and null mutants of nearly all components have been characterized in detail. Undoubtedly, activation of adenylyl cyclase is the most complex, involving G-proteins, a soluble protein called CRAC and components of the MAP kinase pathway. Null mutants in this pathway do not aggregate, but can exhibit chemotaxis and develop normally when supplied with exogenous cAMP. The pathways leading to the activation of phospholipase C were identified, but unexpectedly, deletion of the phospholipase C gene has no effect on chemotaxis and development, nor on intracellular Ins(1,4,5)P3 levels; the metabolism of this second messenger will be discussed in some detail. Activation of guanylyl cyclase is G-protein-dependent and essential for chemotaxis. Analysis of a collection of chemotactic mutants reveals that most mutants are defective in either the production or intracellular detection of cGMP, thereby placing this second messenger at the center of chemotactic signal transduction. Analysis of the cAMP-mediated opening of plasma membrane calcium channels in signal transduction mutants suggests that it has two components, one that depends on G-proteins and intracellular cGMP and one that is G-protein-independent.
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PMID:Transduction of the chemotactic cAMP signal across the plasma membrane of Dictyostelium cells. 853 2

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

We have identified a MAP kinase kinase (DdMEK1) that is required for proper aggregation in Dictyostelium. Null mutations produce extremely small aggregate sizes, resulting in the formation of slugs and terminal fruiting bodies that are significantly smaller than those of wild-type cells. Time-lapse video microscopy and in vitro assays indicate that the cells are able to produce cAMP waves that move through the aggregation domains. However, these cells are unable to undergo chemotaxis properly during aggregation in response to the chemoattractant cAMP or activate guanylyl cyclase, a known regulator of chemotaxis in Dictyostelium. The activation of guanylyl cyclase in response to osmotic stress is, however, normal. Expression of putative constitutively active forms of DdMEK1 in a ddmek1 null background is capable, at least partially, of complementing the small aggregate size defect and the ability to activate guanylyl cyclase. However, this does not result in constitutive activation of guanylyl cyclase, suggesting that DdMEK1 activity is necessary, but not sufficient, for cAMP activation of guanylyl cyclase. Analysis of a temperature-sensitive DdMEK1 mutant suggests that DdMEK1 activity is required throughout aggregation at the time of guanylyl cyclase activation, but is not essential for proper morphogenesis during the later multicellular stages. The activation of the MAP kinase ERK2, which is essential for chemoattractant activation of adenylyl cyclase, is not affected in ddmek1 null strains, indicating that DdMEK1 does not regulate ERK2 and suggesting that at least two independent MAP kinase cascades control aggregation in Dictyostelium.
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PMID:The Dictyostelium MAP kinase kinase DdMEK1 regulates chemotaxis and is essential for chemoattractant-mediated activation of guanylyl cyclase. 925 Jun 76

Atrial natriuretic peptide (ANP) regulates a variety of physiological parameters, including the blood pressure and intravascular volume, by interacting with its receptors present on the plasma membrane. ANP receptors are of three subtypes: ANP-A, -B and -C receptors. ANP-A and ANP-B receptors are guanylyl cyclase receptors, whereas ANP-C receptors are coupled to adenylyl cyclase inhibition or phospholipase C activation through inhibitory guanine nucleotide-regulating protein. Unlike other G protein-coupled receptors, ANP-C receptors have a single transmembrane domain and a short cytoplasmic domain of 37 amino acids, the cytoplasmic domain has a structural specificity like those of other single-transmembrane-domain receptors and 37 amino-acid cytoplasmic domain peptide is able to exert is inhibitory effect on adenylyl cyclase. The activation of ANP-C receptor by C-ANP(4-23) (a ring-deleted peptide of ANP) and C-type natriuretic peptide inhibits the mitogen-activated protein kinase activity stimulated by endothelin-3, platelet-derived growth factor and phorbol-12 myristate 13-acetate. C-ANP also inhibits mitogen-induced stimulation of DNA synthesis, indicating that the ANP-C receptor plays a role in cell proliferation through an inhibition of mitogen-activated protein kinase and suggesting that the ANP-C receptor might also be coupled to other signal transduction mechanism(s) or that there might be an interaction of the ANP-C receptor with some other signalling pathways. ANP receptor binding is decreased in most organs in hypertensive subjects and hypertensive animals. This decrease is consistent with there being fewer guanylyl cyclase-coupled receptors in the kidney and vasculature and selective inhibition of the ANP-C receptor in the thymus and spleen. Platelet ANP-C receptors are decreased in number in hypertensive patients and spontaneously hypertensive rats. ANP-A, -B and -C receptors are decreased in number in deoxycorticosterone acetate-salt-treated kidneys and vasculature; however, the responsiveness of adenylyl cyclase to ANP is augmented in the vasculature and heart and is attenuated completely in platelets. These alterations in ANP receptor subtypes may be related to the pathophysiology of hypertension. Several hormones such as angiotensin II, ANP and catecholamines, the levels of which are increased in hypertension, downregulate or upregulate ANP-C receptors and ANP-C receptor-mediated inhibition of adenylyl cyclase. It can be suggested that the antihypertensive action of several types of drugs such as angiotensin converting enzyme inhibitors, angiotensin type 1 receptor antagonists and beta2-adrenergic antagonists may partly be attributed to their ability to modulate the expression and function of the ANP-C receptor.
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PMID:Atrial natriuretic peptide-C receptor and membrane signalling in hypertension. 928 Feb 3

1. The role of nitric oxide (NO) in the control of cell growth is controversial since both stimulation and (more often) inhibition have been demonstrated in various cell types. In order to reinvestigate the problem and identify the sites of NO action, we have employed murine NIH-3T3 fibroblasts overexpressing epidermal growth factor (EGF) receptors. 2. The effects of four structurally-unrelated NO donors: S-nitroso-N-acetyl penicillamine, S-nitroso-L-glutathione, 3-morpholinosydnonimine and isosorbide dinitrate (0.01-3 mM) on EGF (10 nM)-stimulated cell growth were estimated by both thymidine incorporation and the colorimetric MTT assay, while those of a messenger generated in response to NO, cyclic GMP, were revealed by the use of 8-Br cyclic GMP (0.01-3 mM) as well as of blockers of guanylyl cyclase and cyclic GMP-dependent kinase I. 3. Studies were focused on: (i) multiple signalling events, including receptor-induced tyrosine phosphorylations, phosphorylation of mitogen-activated protein kinase, activation of the AP-1 transcription complex and deoxyribonucleotide synthesis; (ii) the progression through the cell cycle, dissected out by the use of staurosporine (1 nM), lovastatin (10 microM), mimosine (200 microM), hydroxyurea (1 mM) and nocodazole (1.5 microM). 4. NO was found to have no effects on the phosphorylation events of the growth factor cascade. In contrast, later processes were modified by the messenger but with opposite effects. 5. A cyclic GMP-dependent stimulation of growth was shown to be sustained in part by the activation of the AP-1 transcription complex, while a predominant, cyclic GMP-independent inhibition was found to be mediated by both the negative regulation of ribonucleotide reductase and the marked slowing down of the cell cycle occurring at early and late G1 and during the S phase. 6. Although multiple and apparently conflicting, the effects of NO here described could work coordinately in a general programme of cell growth regulation. In particular, the cyclic GMP-dependent actions might function as rapid modulatory events, while the effects on cell cycle might operate collectively as a multi-switch process whenever growth inhibition is required.
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PMID:Nitric oxide effects on cell growth: GMP-dependent stimulation of the AP-1 transcription complex and cyclic GMP-independent slowing of cell cycling. 937 65

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 fibroblast, a cell central to effective wound remodeling, not only contains various growth factor receptors but also high activities of a guanylyl cyclase receptor (GC-B). Here we demonstrate that marked elevations of cyclic GMP induced by C-type natriuretic peptide (CNP), the ligand of GC-B, blocks activation of the mitogen-activated protein kinase cascade in fibroblasts. We also show that platelet-derived growth factor, fibroblast growth factor, serum, or Na3VO4 rapidly (within 5 min) and extensively (up to 85% inhibition) disrupt CNP-dependent elevations of cyclic GMP. In addition, the mitogens also lower cyclic GMP concentrations (50% decrease) in cells not treated with CNP. Cytoplasmic forms of guanylyl cyclase, in contrast to the CNP-stimulated pathway, are not antagonized by the various mitogens. The effects of the mitogens on cellular cyclic GMP are fully explained by a direct and stable inactivation of GC-B. Homogenates obtained from fibroblasts treated with or without the various mitogens contain equivalent amounts of GC-B protein, but both ligand-dependent and ligand-independent activity are markedly (up to 90% inhibition of CNP-dependent activity) decreased after mitogen addition. The stable inactivation is correlated with the dephosphorylation of phosphoserine and phosphothreonine residues of the cyclase receptor. These results not only establish a specific and reciprocal antagonistic relationship between mitogen-activated and GC-B-regulated signaling pathways in the fibroblast but also suggest that one of the earliest events following mitogen activation of a fibroblast is an interruption of cyclic GMP production from this receptor.
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PMID:Reciprocal antagonism coordinates C-type natriuretic peptide and mitogen-signaling pathways in fibroblasts. 993 30

Atrial natriuretic factor (ANF) inhibits proliferation in non-myocardial cells and is thought to be anti-hypertrophic in cardiomyocytes. We investigated the possibility that the anti-hypertrophic actions of ANF involved the mitogen-activated protein kinase signal transduction cascade. Cultured neonatal rat ventricular myocytes treated for 48 h with the alpha(1)-adrenergic agonist phenylephrine (PE) had an 80% increase in cross-sectional area (CSA). ANF alone had no effect but inhibited PE-induced increases in CSA by approximately 50%. The mitogen-activated protein kinase/ERK kinase (MEK) inhibitor PD098059 minimally inhibited PE-induced increases in CSA, but it completely abolished ANF-induced inhibition of PE-induced increases. ANF-induced extracellular signal-regulated protein kinase (ERK) nuclear translocation was also eliminated by PD098059. ANF treatment caused MEK phosphorylation and activation but failed to activate any of the Raf isoforms. ANF induced a rapid increase in ERK phosphorylation and in vitro kinase activity. PE also increased ERK activity, and the combined effect of ANF and PE appeared to be additive. ANF-induced ERK phosphorylation was eliminated by PD098059. ANF induced minimal phosphorylation of JNK or p38, indicating that its effect on ERK was specific. ANF-induced activation of ERK was mimicked by cGMP analogs, suggesting that ANF-induced ERK activation involves the guanylyl cyclase activity of the ANF receptor. These data suggest that there is an important linkage between cGMP signaling and the mitogen-activated protein kinase cascade and that selective ANF activation of ERK is required for the anti-hypertrophic action of ANF. Thus, ANF expression might function as the natural defense of the heart against maladaptive hypertrophy through its ability to activate ERK.
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PMID:Extracellular signal-regulated protein kinase activation is required for the anti-hypertrophic effect of atrial natriuretic factor in neonatal rat ventricular myocytes. 1045 58

We have examined the effect of atrial natriuretic peptide (ANP) and its guanylyl cyclase/natriuretic peptide receptor-A (NPRA) on mitogen-activated protein kinase/extracellular signal-regulated kinase 2 (MAPK/ERK2) activity in rat mesangial cells overexpressing NPRA. Agonist hormones such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiotensin II (ANG II), and endothelin-1 (ET-1) stimulated 2.5- to 3.5-fold immunoreactive MAPK/ERK2 activity in these cells. ANP inhibited agonist-stimulated activity of MAPK/ERK2 by 65-75% in cells overexpressing NPRA, whereas in vector-transfected cells, its inhibitory effect was only 18-20%. NPRA antagonist A71915 and KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG) completely reversed the inhibitory effect of ANP on MAPK/ERK2 activity. ANP also inhibited the PDGF-stimulated [(3)H]thymidine uptake by almost 70% in cells overexpressing NPRA, as compared with only 20-25% inhibition in vector-transfected cells. These results demonstrate that ANP/NPRA system negatively regulates MAPK/ERK2 activity and proliferation of mesangial cells in a PKG-dependent manner.
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PMID:Natriuretic peptide receptor-A negatively regulates mitogen-activated protein kinase and proliferation of mesangial cells: role of cGMP-dependent protein kinase. 1079 5

NO, produced from l-arginine in a reaction catalyzed by NO synthase, is an endogenous free radical with multiple functions in mammalian cells. Here, we demonstrate that endogenously produced NO can suppress c-Jun N-terminal kinase (JNK) activation in intact cells. Treatment of BV-2 murine microglial cells with IFN-gamma induced endogenous NO production, concomitantly suppressing JNK1 activation. Similarly, IFN-gamma induced suppression of JNK1 activation in RAW264.7 murine macrophage cells and rat alveolar macrophages. The IFN-gamma-induced suppression of JNK1 activation in BV-2, RAW264.7, or rat alveolar macrophage cells was completely prevented by N(G)-nitro-l-arginine, a NO synthase inhibitor. Interestingly, the IFN-gamma-induced suppression of JNK1 activation was not affected by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of guanylyl cyclase. 8-Bromo-cGMP, a membrane-permeant analogue of cGMP, did not change JNK1 activation in intact cells either. In contrast, S-nitro-N-acetyl-dl-penicillamine (SNAP), a NO donor, inhibited JNK1 activity in vitro. Furthermore, a thiol reducing agent, DTT, reversed not only the in vitro inhibition of JNK1 activity by SNAP but also the in vivo suppression of JNK1 activity by IFN-gamma. Substitution of serine for cysteine-116 in JNK1 abolished the inhibitory effect of IFN-gamma or SNAP on JNK1 activity in vivo or in vitro, respectively. Moreover, IFN-gamma enhanced endogenous S-nitrosylation of JNK1 in RAW264.7 cells. Collectively, our data suggest that endogenous NO mediates the IFN-gamma-induced suppression of JNK1 activation in macrophage cells by means of a thiol-redox mechanism.
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PMID:Nitric oxide negatively regulates c-Jun N-terminal kinase/stress-activated protein kinase by means of S-nitrosylation. 1112 Oct 10


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