Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor alpha (TNF alpha) activates the stress-activated protein kinases (SAPKs, also known as Jun nuclear kinases or JNKs) resulting in the stimulation of AP-1-dependent gene transcription and induces the translocation of NF kappa B to the nucleus resulting in the stimulation of NF kappa B-dependent gene transcription. A potential second messenger for these signaling pathways is ceramide, which is generated when TNF alpha activates sphingomyelinases. We show that treatment of HL-60 human promyelocytic cells with exogenous sphingomyelinase leads to rapid stimulation of JNK/SAPK activity, an effect not mimicked by treatment with phospholipase A2, C, or D. Further, JNK/SAPK activity is stimulated 2.7- and 2.8-fold, respectively, in cells exposed to C2-ceramide (5 microM) or TNF alpha (10 ng/ml). The prolonged stimulation of this kinase activity by C2-ceramide is similar to that previously reported for TNF alpha. In contrast, the related mitogen-activated protein kinases ERK1 and ERK2 are weakly stimulated following TNF alpha treatment (1.5-fold) and are inhibited by C2-ceramide treatment. TNF alpha also potently stimulates NF-kappa B DNA binding activity and transcriptional activity, but these effects are not mimicked by addition of C2-ceramide or sphingomyelinase to intact cells. Furthermore, TNF alpha, sphingomyelinase, and C2-ceramide induce c-jun, a gene that is stimulated by the ATF-2 and c-Jun transcription factors. These data suggest that ceramide may act as a second messenger for a subset of TNF alpha's biochemical and biological effects.
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PMID:Ceramide activates the stress-activated protein kinases. 755 90

Group II phospholipase A2 (PLA2) is a mediator of inflammation in various disease including glomerulonephritis. We recently found that urinary excretion of PLA2 was increased in patients with mesangial proliferative glomerulonephritis and that interleukin-1 (IL-1) enhanced platelet derived growth factor-stimulated mesangial cell proliferation through the action of group II PLA2 secreted in response to IL-1 stimuli. Here we report signal transducing mechanism through group II PLA2 in mesangial cells. Group II PLA2 (1-15 U/ml) rapidly activated mitogen-activated protein (MAP) kinase. IL-1 beta activated MAP kinase in two phases and the slow activation in the late phase, proceeding in parallel with increased group II PLA2 secretion elicited by IL-1 treatment, was inhibited by the specific antibody raised against group II PLA2. This suggests that the late phase activation of IL-1-induced MAP kinase was mediated, at least in part, by secreted group II PLA2.
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PMID:Group II phospholipase A2 activates mitogen-activated protein kinase in cultured rat mesangial cells. 764 92

The role of mitogen-activated protein (MAP) kinase in the release of arachidonic acid was examined in a mutated mast cell (RBL-2H3(m1)) line that expressed both native Fc epsilon R1 and the G protein-coupled muscarinic m1 receptor. Stimulation of these cells with Ag, carbachol, Ca(2+)-ionophore, or thapsigargin resulted in the phosphorylation of Raf1, MEK1, p42mapk MAP kinase, and the recently cloned cytosolic phospholipase A2 (PLA2) and increased activities of both MAP kinase and PLA2, as well as release of arachidonic acid. Because this cascade of reactions was inhibited by guanosine 5'-(2-thiodiphosphate), it appeared to be dependent on a GTP-binding protein(s). These reactions, however, were not dependent on protein kinase C; the cascade was totally resistant to the actions of a selective protein kinase C inhibitor, Ro31-7549, whereas release of the secretory granule marker, hexosaminidase, was blocked by this agent. Differences between the stimulatory pathways for release of arachidonic acid and hexosaminidase were evident also from the effects of the kinase inhibitor, quercetin. The above cascade of reactions, including release of arachidonic acid, was inhibited by 50% with approximately 5 microM quercetin, whereas secretion was inhibited only at higher concentrations of inhibitor. Moreover, inhibition of the activation of MAP kinase and release of arachidonic acid were closely correlated. This and previous findings suggested that release of arachidonic acid was attributable to the regulation of cytosolic PLA2 by MAP kinase (for activation of PLA2) and Ca2+ (for association of PLA2 with the membrane), whereas release of hexosaminidase was regulated primarily by Ca2+ and protein kinase C.
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PMID:Activation of the mitogen-activated protein kinase/cytosolic phospholipase A2 pathway in a rat mast cell line. Indications of different pathways for release of arachidonic acid and secretory granules. 773 Jun 40

The thrombin receptor agonist peptide SFLLRN was less effective than thrombin in eliciting the liberation of arachidonic acid and the generation of thromboxane A2 by human platelets. We found that while SFLLRN evokes an initial transient increase in cystolic free calcium concentration ([Ca2+]i) of similar magnitude as that caused by thrombin, the SFLLRN-induced elevation of [Ca2+]i declines more rapidly to near resting levels than that evoked by thrombin, suggesting that disparate levels of [Ca2+]i may contribute to the attenuated arachidonic acid release. Furthermore, we observed that SFLLRN is less effective than thrombin in mediating the "activating" phosphorylation of cytolic phospholipase A2 (cPLA2). Both thrombin and SFLLRN rapidly and transiently activated kinases that phosphorylate the 21-residue synthetic peptide Thr669 derived from the epidermal growth factor receptor, but the maximal activation of proline-directed kinases by SFLLRN was less pronounced than that by thrombin. MonoQ chromatography and immunoblot analysis of extracts from stimulated platelets revealed that while thrombin induced a prominent activation of the mitogen-activated protein kinases ERK1 and ERK2, SFLLRN completely failed to do so. On the other hand, SFLLRN, like thrombin, stimulated the activity of a proline-directed kinase distinct from ERK1/2, but the activation of this kinase was less pronounced following stimulation of platelets with SFLLRN compared with thrombin. We conclude 1) that the partial activation of cPLA2 and the subsequent attenuated mobilization of arachidonic acid in response to SFLLRN may be the consequence of a less prolonged elevation of [Ca2+]i and insufficient activation of proline-directed kinase(s) by SFLLRN and 2) that the ability of SFLLRN to mediate the activating phosphorylation of cPLA2 in the absence of ERK1/2 stimulation suggest that, at least in human platelets, proline-directed kinases other than ERK1/2 may phosphorylate and activate cPLA2.
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PMID:Differential activation of cytosolic phospholipase A2 (cPLA2) by thrombin and thrombin receptor agonist peptide in human platelets. Evidence for activation of cPLA2 independent of the mitogen-activated protein kinases ERK1/2. 778 48

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are cytokines with pleiotropic biological activities, exerting a broad range of overlapping biological functions. The redundancy of TNF and IL-1 activities may be based on the utilization of shared key components of intracellular signaling pathways. Two lipid second messengers have been found to transmit TNF and IL-1 intracellular signals: 1,2-diacylglycerol (DAG), generated by a phosphatidylcholine-specific phospholipase C, and ceramide, generated by sphingomyelinase (SMase). DAG is a well established activator of the important signaling system protein kinase C (PKC), which appears to mediate various cellular responses to TNF or IL-1. In addition, it is obvious that DAG also activates other enzyme systems like acidic sphingomyelinase. SMases have been implicated in a number of TNF responses, including stimulation of cell growth and differentiation, as well as triggering cytotoxicity and apoptosis. The metabolic active cleavage product of SMase, ceramide, is a novel multifunctional lipid second messenger capable of inducing various signaling systems. Both cytokines, TNF and IL-1, stimulate a neutral,plasma membrane-associated SMase that leads to stimulation of a protein kinase and eventually to activation of the mitogen-activated protein (MAP) kinase cascade and phospholipase A2. Ceramide is also capable of stimulating a cytosolic protein phosphatase. PKC plays a role in activation of the nuclear transcription factor AP-1, and the DAG-regulated acidic SMase is involved in transducing TNF signals to the cell nucleus via activation of the nuclear transcription factor NF-kappa B.
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PMID:The role of diacylglycerol and ceramide in tumor necrosis factor and interleukin-1 signal transduction. 796 60

The 85-kDa cytoplasmic phospholipase A2 (cPLA2) is the major hormone and growth factor-regulated enzyme that catalyzes release of arachidonic acid in mammalian cells. Activation of cPLA2 requires elevation of intracellular Ca2+ and the phosphorylation of the cPLA2 enzyme by mitogen-activated protein (MAP) kinase. Down-regulation of protein kinase C by phorbol esters or pertussis toxin catalyzed ADP-ribosylation of Gi proteins inhibits thrombin and ATP receptor-stimulated MAP kinase and arachidonic acid release, indicating that functional protein kinase C and Gi proteins are required for G protein regulation of arachidonic acid release. A mutant G alpha i2 subunit having Gly203 mutated to Thr (alpha i2G203T) inhibited thrombin and ATP receptor stimulation of arachidonic acid release independent of adenylyl cyclase inhibition, Ca2+ mobilization, and MAP kinase activation. Overexpression of the wild-type alpha i2 polypeptide or the inactive mutant alpha i2G204A (Gly204 mutated to Ala) polypeptide had no effect on thrombin or ATP receptor stimulation of arachidonic acid release. The phenotype observed with expression of the mutant alpha i2G203T polypeptide defines a role for Gi2 in the control of cPLA2 activity and subsequent arachidonic acid release in addition to the regulation of intracellular Ca2+ levels and MAP kinase activity.
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PMID:Expression of a mutant Gi2 alpha subunit inhibits ATP and thrombin stimulation of cytoplasmic phospholipase A2-mediated arachidonic acid release independent of Ca2+ and mitogen-activated protein kinase regulation. 829 38

Invasion of host cells is essential for the pathogenicity of Salmonella. We have recently shown that invasion of cultured epithelial cells by S. typhimurium is accompanied by activation of the epidermal growth factor receptor. In this report we show that S. typhimurium invasion stimulated a rapid increase in the levels of free intracellular calcium ([Ca2+]i) in cultured epithelial cells. Mutants defective in invasion were unable to induce these calcium fluxes, and addition of calcium antagonists blocked wild-type S. typhimurium entry. These results indicate that [Ca2+]i increase is required for bacterial entry. Further analysis demonstrated that phospholipase A2 and 5-lipoxygenase activities resulting in production of leukotrienes are required for bacterial entry. Addition of the leukotriene D4 to Henle-407 cells caused both an increase in [Ca2+]i and the internalization of an invasion-defective mutant of S. typhimurium. Furthermore, S. typhimurium caused the activation of mitogen-activated protein (also known as extracellular signal-regulated protein) kinase in infected cells.
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PMID:Signal transduction and invasion of epithelial cells by S. typhimurium. 838 66

It is well known that external load plays a critical role in determining cardiac muscle mass and its phenotype, but little is known as to how mechanical load is transduced into intracellular signals regulating gene expression. To address this question we analyzed the 'mechano-transcription' coupling process using an in vitro model of load-induced cardiac hypertrophy, in which a stretch of rat cardiac myocytes, grown on a deformable substrate, causes a rapid induction of immediate-early genes followed by growth (hypertrophic) response. We report here that cell stretch rapidly activates a plethora of second messenger pathways, including tyrosine kinases, p21ras, mitogen-activated protein (MAP) kinases, S6 kinases (pp90RSK), protein kinase C, phospholipase C, phospholipase D, and probably the phospholipase A2 and P450 pathways. In contrast, the cAMP pathway is not activated significantly by stretch. The signals generated by these second messengers appear to converge into activation of the p67SRF-p62TCF complex via the serum response element, causing induction of c-fos. The stretch response may involve an autocrine or paracrine mechanism, because stretch-conditioned medium, when transferred to non-stretched myocytes, mimicked the effect of stretch. These results indicate that mechanical load causes rapid activation of multiple second messenger systems, which may in turn initiate a cascade of hypertrophic response of cardiac myocytes.
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PMID:Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. 838 10

A paradigm has been established whereby mutant tyrosine kinase receptors such as the v-erbB and v-fms gene products function as oncoproteins in the absence of ligand. A spontaneously occurring deletional mutant of the human epidermal growth factor receptor (EGFR-vIII) has been isolated from astrocytic neoplasms and transforms NIH3T3 cells in the absence of ligand. The EGFRvIII is constitutively complexed with the majority of cellular GRB2, suggesting a link to the Ras-Mitogen-activated protein (MAP) kinase pathway (D. Moscatello, R. B. Montgomery, P. Sundareshan, H. McDanel, M. Y. Wong, and A. J. Wong, submitted for publication). In this report, we document that expression of EGFRvIII in fibroblasts is associated with downstream activation of mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (MEK) and modest activation of p42 and p44 MAP kinases. The presence of EGFRvIII suppresses activation of p42 and p44 MAP kinases by phorbol 12-myristate 13-acetate (PMA) and serum; however, MEK activation by PMA is not suppressed by EGFRvIII. Basal and PMA-stimulated MAP kinase activity in EGFRvIII-transfected cells is augmented by the tyrosine phosphatase inhibitor sodium vanadate. EGFR-vIII is capable of transducing downstream signals through MAP kinase as evidenced by activation of cytoplasmic phospholipase A2 at levels similar to that induced by intact EGFR. Our results suggest that EGFR-vIII constitutively activates downstream signal transduction through MAP kinase, and this chronic stimulation of the MAP kinase pathway may represent one means by which mutant EGFR transduces an oncogenic signal.
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PMID:Differential modulation of mitogen-activated protein (MAP) kinase/extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor. 853 Apr 89

In the present study, we investigated the mechanism of phenylephrine (alpha-1-adrenergic receptor agonist)-induced arachidonic acid release in Japanese white rabbit aortic smooth muscle cells (SMC). When introduced into permeabilized smooth muscle cells, guanosine S-[gamma-thio] triphosphate (GTPgamma S), which activates GTP-binding proteins (G proteins), stimulated arachidonic acid (AA) release. Neomycin, an inhibitor of phosphoinositide (PI) turnover, was almost without effect on GTP[gamma S] stimulated AA release. In addition, pertussis toxin (PT) partially inhibited phenylephrine-stimulated AA release, suggesting that IAP (Islet activating protein)-sensitive G proteins mediate this process. Phenylephrine-stimulated AA release was also inhibited by decreased extracellular calcium and aristolochic acid, suggesting a role for a phospholipase A2 (PLA2). Next PLA2 is reported to be a substrate for mitogen-activated protein (MAP) kinase. We examined the effect of phenylephrine on MAP kinase and c-jun N-terminal kinase (JNK) phosphorylation. Phenylephrine didn't induce phosphorylation of MAP kinase, but did induce phosphorylation of JNK. In addition, cells which were pretreated with PT inhibited the phosphorylation of JNK. These results suggest that IAP-sensitive G protein is involved in the coupling between alpha1-adrenergic receptor (AR) and PLA2 in cultured rabbit aortic SMCs, and that the alpha1-AR-induced AA release is mediated by JNK.
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PMID:alpha-1-Adrenergic receptor stimulation causes arachidonic acid release through pertussis toxin-sensitive GTP-binding protein and JNK activation in rabbit aortic smooth muscle cells. 860 77


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