Tumour necrosis factor-α-induced phosphorylation and activation of cytosolic phospholipase A2 are abrogated by an inhibitor of the p38 mitogen-activated protein kinase cascade in human neutrophils

The role of the newly identified p38 mitogen-activated protein kinase (MAP kinase) in terminally differentiated cells, such as human neutrophils, is totally unknown. In order to examine the possible role of this MAP kinase in the phosphorylation and activation of cytoplasmic phospholipase A2 (cPLA2), we tested the effect of the recently synthesized inhibitor of p38 MAP kinase, SB 203580, on the phosphorylation and activation of both p38 MAP kinase and cPLA2. We found that while tumour necrosis factor-α (TNF-α)-stimulated tyrosine phosphorylation of p38 MAP kinase is affected only slightly by SB 203580, its stimulated kinase activity is greatly reduced in human neutrophils in suspension treated with this inhibitor. Furthermore, the TNF-α-stimulated phosphorylation and activation of cPLA2 are completely abolished in cells treated with SB 203580. Based on these data, it is reasonable to conclude that an SB 203580-sensitive kinase, or kinases and/or phosphatases, are involved in the phosphorylation and activation of cPLA2 in intact human neutrophils in suspension stimulated by TNF-α. The possible role of the p38 MAP kinase cascade in the phosphorylation and activation of cPLA2 is discussed.

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Interaction of Rac Exchange Factors Tiam1 and Ras-GRF1 with a Scaffold for the p38 Mitogen-Activated Protein Kinase Cascade

Molecular and Cellular Biology ◽

10.1128/mcb.22.12.4073-4085.2002 ◽

2002 ◽

Vol 22 (12) ◽

pp. 4073-4085 ◽

Cited By ~ 131

Author(s):

Rachel J. Buchsbaum ◽

Beth A. Connolly ◽

Larry A. Feig

Keyword(s):

Map Kinase ◽

P38 Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Nucleotide Exchange ◽

Rac Gtpase ◽

Signaling Specificity ◽

Map Kinase Cascade ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

In Cells

ABSTRACT Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-terminal region of both proteins binds to the scaffold protein IB2/JIP2. IB2/JIP2 is a scaffold for the p38 mitogen-activated protein (MAP) kinase cascade because it binds to the Rac target MLK3, the MAP kinase kinase MKK3, and the p38 MAP kinase. Expression of IB2/JIP2 in cells potentiates the ability of Tiam1 or Ras-GRF1 to activate the p38 MAP kinase cascade but not the Jnk MAP kinase cascade. In addition, Tiam1 or Ras-GRF1 binding to IB2/JIP2 increases the association of the components of the p38 MAP kinase signaling cassette with IB2/JIP2 in cells and activates scaffold-associated p38. These findings imply that Tiam1 and Ras-GRF1 can contribute to Rac signaling specificity by their ability to form a complex with a scaffold that binds components of one of the many known Rac effector pathways.

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Legionella pneumophila Suppresses Macrophage Interleukin-12 Production by Activating the p42/44 Mitogen-Activated Protein Kinase Cascade

Infection and Immunity ◽

10.1128/iai.71.11.6672-6675.2003 ◽

2003 ◽

Vol 71 (11) ◽

pp. 6672-6675 ◽

Cited By ~ 9

Author(s):

Kazuto Matsunaga ◽

Hiroyuki Yamaguchi ◽

Thomas W. Klein ◽

Herman Friedman ◽

Yoshimasa Yamamoto

Keyword(s):

Map Kinase ◽

Legionella Pneumophila ◽

Kinase Inhibitors ◽

Selective Inhibition ◽

P38 Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Interleukin 12 ◽

Map Kinase Cascade ◽

Mitogen Activated Protein ◽

Kinase Cascade

ABSTRACT A possible involvement of the mitogen-activated protein (MAP) kinase cascade in the inhibition of macrophage interleukin-12 (IL-12) production by Legionella pneumophila infection was examined. The results of MAP kinase inhibition by p42/44 and p38 MAP kinase inhibitors and of p42/44 MAP kinase activity assays indicate that L. pneumophila infection of macrophages causes a selective inhibition of lipopolysaccharide-induced IL-12 production by activating the p42/44 MAP kinase cascade. In addition, it was also revealed that the p38 MAP kinase may be important for the production of IL-12 but not for the inhibition caused by L. pneumophila infection.

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Ionomycin causes activation of p38 and p42/44 mitogen-activated protein kinases in human neutrophils

AJP Cell Physiology ◽

10.1152/ajpcell.2001.281.1.c350 ◽

2001 ◽

Vol 281 (1) ◽

pp. C350-C360 ◽

Cited By ~ 42

Author(s):

David J. Elzi ◽

A. Jason Bjornsen ◽

Todd MacKenzie ◽

Travis H. Wyman ◽

Christopher C. Silliman

Keyword(s):

Map Kinase ◽

Map Kinases ◽

P38 Map Kinase ◽

Polymorphonuclear Neutrophils ◽

Human Neutrophils ◽

Kinase Activation ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Activating Transcription Factor

Many receptor-linked agents that prime or activate the NADPH oxidase in polymorphonuclear neutrophils (PMNs) elicit changes in cytosolic Ca2+concentration and activate mitogen-activated protein (MAP) kinases. To investigate the role of Ca2+in the activation of p38 and p42/44 MAP kinases, we examined the effects of the Ca2+-selective ionophore ionomycin on priming and activation of the PMN oxidase. Ionomycin caused a rapid rise in cytosolic Ca2+that was due to both a release of cytosolic Ca2+stores and Ca2+influx. Ionomycin also activated (2 μM) and primed (20–200 nM) the PMN oxidase. Dual phosphorylation of p38 MAP kinase and phosphorylation of its substrate activating transcription factor-2 were detected at ionomycin concentrations that prime or activate the PMN oxidase, while dual phosphorylation of p42/44 MAP kinase and phosphorylation of its substrate Elk-1 were elicited at 0.2–2 μM. SB-203580, a p38 MAP kinase antagonist, inhibited ionomycin-induced activation of the oxidase (68 ± 8%, P < 0.05) and tyrosine phosphorylation of 105- and 72-kDa proteins; conversely, PD-98059, an inhibitor of MAP/extracellular signal-related kinase 1, had no effect. Treatment of PMNs with thapsigargin resulted in priming of the oxidase and activation of p38 MAP kinase. Chelation of cytosolic but not extracellular Ca2+completely inhibited ionomycin activation of p38 MAP kinase, whereas chelation of extracellular Ca2+abrogated activation of p42/44 MAP kinase. These results demonstrate the importance of changes in cytosolic Ca2+for MAP kinase activation in PMNs.

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Role of a Mitogen-Activated Protein Kinase Cascade in Ion Flux-Mediated Turgor Regulation in Fungi

Eukaryotic Cell ◽

10.1128/ec.5.3.480-487.2006 ◽

2006 ◽

Vol 5 (3) ◽

pp. 480-487 ◽

Cited By ~ 34

Author(s):

Roger R. Lew ◽

Natalia N. Levina ◽

Lana Shabala ◽

Marinela I. Anderca ◽

Sergey N. Shabala

Keyword(s):

Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Wild Type ◽

Turgor Regulation ◽

Map Kinase Cascade ◽

Protein Map ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

Protein Kinase Cascade

ABSTRACT Fungi normally maintain a high internal hydrostatic pressure (turgor) of about 500 kPa. In response to hyperosmotic shock, there are immediate electrical changes: a transient depolarization (1 to 2 min) followed by a sustained hyperpolarization (5 to 10 min) prior to turgor recovery (10 to 60 min). Using ion-selective vibrating probes, we established that the transient depolarization is due to Ca2+ influx and the sustained hyperpolarization is due to H+ efflux by activation of the plasma membrane H+-ATPase. Protein synthesis is not required for H+-ATPase activation. Net K+ and Cl− uptake occurs at the same time as turgor recovery. The magnitude of the ion uptake is more than sufficient to account for the osmotic gradients required for turgor to return to its original level. Two osmotic mutants, os-1 and os-2, homologs of a two-component histidine kinase sensor and the yeast high osmotic glycerol mitogen-activated protein (MAP) kinase, respectively, have lower turgor than the wild type and do not exhibit the sustained hyperpolarization after hyperosmotic treatment. The os-1 mutant does not exhibit all of the wild-type turgor-adaptive ion fluxes (Cl− uptake increases, but net K+ flux barely changes and net H+ efflux declines) (os-2 was not examined). Both os mutants are able to regulate turgor but at a lower level than the wild type. Our results demonstrate that a MAP kinase cascade regulates ion transport, activation of the H+-ATPase, and net K+ and Cl− uptake during turgor regulation. Other pathways regulating turgor must also exist.

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Functional Role of p38 Mitogen Activated Protein Kinase in Platelet Activation induced by a Thromboxane A2 Analogue and by 8-iso-prostaglandin F2 α

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613101 ◽

2002 ◽

Vol 87 (05) ◽

pp. 888-898 ◽

Cited By ~ 23

Author(s):

Stefania Gaino ◽

Valeria Zuliani ◽

Rosa Tommasoli ◽

Donatella Benati ◽

Riccardo Ortolani ◽

...

Keyword(s):

Map Kinase ◽

Platelet Activation ◽

Tyrosine Kinases ◽

Actin Polymerization ◽

Shape Change ◽

Specific Inhibitor ◽

P38 Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Kinase Phosphorylation

SummaryWe investigated similarities in the signaling pathways elicited by the F2 isoprostane 8-iso-PGF2α and by low doses of U46619 to induce platelet activation. Both 0.01-0.1 µmol/L U46619 and 0.01-1 µmol/L 8-isoPGF2α triggered shape change and filopodia extension, as well as adhesion to immobilized fibrinogen of washed platelets. At these doses the two platelet agonists failed to trigger secretion and aggregation, which were however induced by higher doses of U46619 (0.1-1 µmol/L). SB203580 (1-10 µmol/L), a specific inhibitor of the p38 mitogen activated protein (MAP) kinase blunted platelet shape change and adhesion induced by 0.05-1 µmol/L 8-iso-PGF2α and by 0.01 µmol/L U46619. These platelet responses were also inhibited by 20 µmol/L cytochalasin D, an inhibitor of actin polymerization, and 50 µmol/L piceatannol, an inhibitor of the Syk tyrosine kinases. Both 8-iso-PGF2α and U46619-induced p38 MAP kinase phosphorylation in suspended platelets and this was inhibited by piceatannol, indicating that Syk activation occurs upstream p38 MAP kinase phosphorylation. These findings suggest that the signaling pathway triggered by both 8-iso-PGF2α and low concentrations of U46619 to induce platelet adhesion and shape change implicates Syk, the p38 MAP kinase, and actin polymerization.

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Role of Mitogen-Activated Protein Kinase Pathway in Prostaglandin F2α-Induced Rat Puerperal Uterine Contraction

Endocrinology ◽

10.1210/endo.138.8.5305 ◽

1997 ◽

Vol 138 (8) ◽

pp. 3103-3111 ◽

Cited By ~ 31

Author(s):

Masahide Ohmichi ◽

Koji Koike ◽

Akiko Kimura ◽

Kanji Masuhara ◽

Hiromasa Ikegami ◽

...

Keyword(s):

Map Kinase ◽

Uterine Contraction ◽

Prostaglandin F2α ◽

Mek Inhibitor ◽

Biological Action ◽

Mitogen Activated Protein Kinase ◽

Myometrial Cells ◽

Mitogen Activated Protein ◽

Kinase Pathway

Abstract In this study, prostaglandin (PG) F2α was found to activate mitogen-activated protein (MAP) kinase and MAP kinase kinase (MEK) in cultured rat puerperal uterine myometrial cells. PGF2α stimulation also led to an increase in phosphorylation of raf-1, son of sevenless (SOS), and Shc. Furthermore, we examined the mechanism by which PGF2α induced MAP kinase phosphorylation. Both pertussis toxin (10 ng/ml), which inactivates Gi/Go proteins, and expression of a peptide derived from the carboxyl terminus of the β-adrenergic receptor kinase 1 (βARK1), which specifically blocks signaling mediated by the βγ subunits of G proteins, blocked the PGF2α-induced activation of MAP kinase. Ritodrine (1 μm), which is known to relax uterine muscle contraction, attenuated PGF2α-induced tyrosine phosphorylation of MAP kinase. Moreover, to examine the role of MAP kinase pathway in uterine contraction, an inhibitor of MEK activity, PD098059, was used. Although MEK inhibitor had no effect on PGF2α-induced calcium mobilization, this inhibitor partially inhibited PGF2α-induced uterine contraction. These results provide evidence that PGF2α stimulates the MAP kinase signaling pathway in cultured rat puerperal uterine myometrial cells through Gβγ protein, suggesting that this new pathway may play an important role in the biological action of PGF2α on these cells.

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Tumor necrosis factor α (TNF-α)-induced RANTES chemokine expression via activation of NF-κB and p38 MAP kinase: roles of TNF-α in alcoholic liver diseases

Journal of Hepatology ◽

10.1016/s0168-8278(02)00456-7 ◽

2003 ◽

Vol 38 (4) ◽

pp. 483-489 ◽

Cited By ~ 17

Author(s):

Fuminori Hirano ◽

Keiji Komura ◽

Etsushi Fukawa ◽

Isao Makino

Keyword(s):

Tumor Necrosis Factor ◽

Map Kinase ◽

Liver Diseases ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

P38 Map Kinase ◽

Tnf Α ◽

Factor Α ◽

Alcoholic Liver Diseases ◽

Necrosis Factor

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The Ustilago maydis ubc4 and ubc5 Genes Encode Members of a MAP Kinase Cascade Required for Filamentous Growth

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi.2000.13.7.781 ◽

2000 ◽

Vol 13 (7) ◽

pp. 781-786 ◽

Cited By ~ 81

Author(s):

David L. Andrews ◽

John D. Egan ◽

María E. Mayorga ◽

Scott E. Gold

Keyword(s):

Map Kinase ◽

Ustilago Maydis ◽

Filamentous Growth ◽

Mitogen Activated Protein Kinase ◽

Genetic Determinants ◽

Map Kinase Cascade ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

Suppressor Mutants ◽

Corn Smut

Ustilago maydis, the causal agent of corn smut disease, displays dimorphic growth in which it alternates between a budding haploid saprophyte and a filamentous dikaryotic pathogen. We are interested in identifying the genetic determinants of filamentous growth and pathogenicity in U. maydis. To do this we have taken a forward genetic approach. Earlier, we showed that haploid adenylate cyclase (uac1) mutants display a constitutively filamentous phenotype. Mutagenesis of a uac1 disruption strain allowed the isolation of a large number of budding suppressor mutants. These mutants are named ubc, for Ustilago bypass of cyclase, as they no longer require the production of cyclic AMP (cAMP) to grow in the budding morphology. Complementation of a subset of these suppressor mutants led to the identification of the ubc4 and ubc5 genes, which are required for filamentous growth and encode a MAP (mitogen-activated protein) kinase kinase kinase and a MAP kinase kinase, respectively. Evidence suggests that they are important in the pheromone response pathway and in pathogenicity. These results further support an important interplay of the cAMP and MAP kinase signal transduction pathways in the control of morphogenesis and pathogenicity in U. maydis.

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