Phosphorylation and Activation of Cytosolic Phospholipase A<sub>2</sub> by 38‐kDa Mitogen‐Activated Protein Kinase in Collagen‐Stimulated Human Platelets

Börsch-Haubold, Angelika; Kramer, Ruth M.; Watson, Steve P.

doi:10.1111/j.1432-1033.1997.t01-1-00751.x

Cited by 148 publications

(145 citation statements)

References 49 publications

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“…p38 MAP kinase, which plays a role in the stress-stimulated signal transduction pathway, has been reported to serve as an activator for cPLA 2 via its phosphorylation in thrombin-or collagen-stimulated platelets (9,32). Therefore, we examined the contribution of p38 MAP kinase to cPLA 2 activation and to arachidonic acid release under the experimental conditions used here.…”

Section: Resultsmentioning

confidence: 99%

“…In glomerular disorders, ROS are generated by several inflammatory cells including neutrophils, monocytes, and macrophages gathered in the inflamed glomeruli, and also by the mesangial cell itself (7,9,10). Previous studies revealed that the intracellular generation of ROS or exposure to H 2 O 2 (a major species of ROS) leads to an increase in PGE 2 production and arachidonic acid release in rat renal glomeruli and rat mesangial cells (2,5,48).…”

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confidence: 99%

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ERK and p38 MAP kinase are involved in arachidonic acid release induced by H₂O₂and PDGF in mesangial cells

Hayama

Inoue

Akiba

et al. 2002

American Journal of Physiology-Renal Physiology

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-Increased prostaglandin production is implicated in the pathogenesis of glomerular disease. With this consideration, we examined the combined effects of reactive oxygen species and platelet-derived growth factor (PDGF), which might initiate glomerular dysfunction, on arachidonic acid release and cytosolic phospholipase A2 (cPLA2) activation in rat mesangial cells. H2O2-induced release of arachidonic acid was enhanced by PDGF, which by itself had little effect on the release, and the enhancement was completely inhibited by a cPLA2 inhibitor. The phosphorylation of cPLA2, extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein (MAP) kinase was upregulated by H2O2 or PDGF alone and except for ERK was enhanced further by the two in combination. The release of arachidonic acid induced by PDGF together with H2O2 was inhibited partially by an inhibitor of ERK or p38 MAP kinase and completely when the two inhibitors were combined; the inhibitory pattern was similar to that for the phosphorylation of cPLA2. These results suggest that the ERK and p38 MAP kinase pathways are involved in the increase in cPLA2 activation and arachidonic acid release induced by PDGF together with H2O2. hydrogen peroxide; p38 mitogen-activated protein kinase; extracellular signal-regulated kinase; cytosolic phospholipase A2; platelet-derived growth factor MESANGIAL CELLS SYNTHESIZE vasodilatory prostaglandins (PGs) such as PGE 2 , which act as relaxing factors and regulate glomerular hemodynamics under physiological conditions. However, an increase in renal PGE 2 production, which is observed in renal diseases such as glomerulonephritis and diabetic glomerulopathy, induces a functional disorder of the mesangium including abnormal glomerular filtration rate and is implicated in the pathogenesis of nephropathy (46,52).Previously, reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ), superoxide anion, and hydroxyl radical were recognized to cause cell injury and therefore be involved in the pathogenesis of various diseases. However, recent observations indicate that ROS cause physiological responses other than pathological responses, including protein phosphorylation, Ca 2ϩ signaling, and the activation of transcription factors by stimulating intracellular signaling systems, thus suggesting that ROS function as second messengers in the signal transduction pathway stimulated by the proinflammatory cytokines interleukin-1␤ and tumor necrosis factor-␣ (21,36,38,50).In glomerular disorders, ROS are generated by several inflammatory cells including neutrophils, monocytes, and macrophages gathered in the inflamed glomeruli, and also by the mesangial cell itself (7, 9, 10). Previous studies revealed that the intracellular generation of ROS or exposure to H 2

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H₂O₂and PDGF in mesangial cells

Hayama

Inoue

Akiba

et al. 2002

American Journal of Physiology-Renal Physiology

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“…It has been widely reported that ERK or p38 directly phosphorylates cytosolic phospholipase A 2 in activated cells and in in vitro assays (48,49) and, with the exception of thrombin-stimulated platelets (50), ERK or p38 has been found to directly regulate the enzymatic activity of cytosolic phospholipase A 2 . Our study, therefore, suggests that fatty acids such as 20:4 6, which are liberated by ligand-stimulated cytosolic phospholipase A 2, may participate in sustaining/amplifying MAP kinase activity and the activity of cytosolic phospholipase A 2 .…”

Section: Resultsmentioning

confidence: 99%

Stimulation of p38 Phosphorylation and Activity by Arachidonic Acid in HeLa Cells, HL60 Promyelocytic Leukemic Cells, and Human Neutrophils

Hii¹,

Huang²,

Bilney³

et al. 1998

Journal of Biological Chemistry

100

101

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Although it is well appreciated that arachidonic acid, a second messenger molecule that is released by ligandstimulated phospholipase A 2 , stimulates a wide range of cell types, the mechanisms that mediate the actions of arachidonic acid are still poorly understood. We now report that arachidonic acid stimulated the appearance of dual-phosphorylated (active) p38 mitogen-activated protein kinase as detected by Western blotting in HeLa cells, HL60 cells, human neutrophils, and human umbilical vein endothelial cells but not Jurkat cells. An increase in p38 kinase activity caused by arachidonic acid was also observed. Further studies with neutrophils show that the stimulation of p38 dual phosphorylation by arachidonic acid was transient, peaking at 5 min, and was concentration-dependent. The effect of arachidonic acid was not affected by either nordihydroguaiaretic acid, an inhibitor of the 5-, 12-, and 15-lipoxygenases or by indomethacin, an inhibitor of cyclooxygenase. Arachidonic acid also stimulated the phosphorylation and/or activity of the extracellular signal-regulated protein kinase and of c-jun N-terminal kinase in a cell-typespecific manner. An examination of the mechanisms through which arachidonic acid stimulated the phosphorylation/activity of p38 and extracellular signal-regulated protein kinase in neutrophils revealed an involvement of protein kinase C. Thus, arachidonic acid stimulated the translocation of protein kinase C ␣, ␤I, and ␤II to a particulate fraction, and the effects of arachidonic acid on mitogen-activated protein kinase phosphorylation/activity were partially inhibited by GF109203X, an inhibitor of protein kinase C. This study is the first to demonstrate that a polyunsaturated fatty acid causes the dual phosphorylation and activation of p38.

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“…However, the nature of the protein kinase(s) involved in the phosphorylation of platelet cPLA 2 , induced by physiological agonists or non-physiological compounds, is still unclear. Particularly, collagen and thrombin activate cPLA 2 by a PKC-independent mechanism [21] and p38 mapk appears to be involved in this process [22,23]. On the other hand, PKC-mediated phosphorylation of cPLA 2 by p42/p44 mapk takes place in platelets treated with phorbol esters and Ca 2 ionophore [24].…”

Section: Discussionmentioning

confidence: 99%

“…The site of this e¡ect is still unknown but it is reasonable to suppose that it does not belong either to the pathways activated by collagen or thrombin, since those are not or little a¡ected by speci¢c PKC inhibitors [6,22], or to that triggered by phorbol esters and Ca 2 because it is blocked by PKC inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Evidence that cytosolic phospholipase A₂ is down‐regulated by protein kinase C in intact human platelets stimulated with fluoroaluminate

et al. 1999

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We reported that protein kinase C (PKC) inhibitors increase the release of arachidonic acid induced by fluoroaluminate (AlF 3 4 ), an unspecific G-protein activator, in intact human platelets. Now we demonstrate that this effect is independent of the extracellular Ca 2+ concentration and that AlF 3 4 -induced release of AA is abolished by BAPTA, an intracellular Ca 2+ chelator, even in the presence of GF 109203X, a specific and potent PKC inhibitor. This compound also blocks the liberation of the secretory phospholipase A 2 in the extracellular medium, indicating that this enzyme is not involved in the potentiation of arachidonic acid by PKC inhibitors. On the other hand, the latter effect is completely abolished by treatment of platelets with AACOCF 3 , a specific inhibitor of cytosolic phospholipase A 2 (cPLA 2 ). These observations indicate that cPLA 2 is responsible for the AlF 3 4 -induced release of arachidonic acid by a mechanism that is down-regulated by PKC.z 1999 Federation of European Biochemical Societies.

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Phosphorylation and Activation of Cytosolic Phospholipase A₂ by 38‐kDa Mitogen‐Activated Protein Kinase in Collagen‐Stimulated Human Platelets

Cited by 148 publications

References 49 publications

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H₂O₂and PDGF in mesangial cells

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H₂O₂and PDGF in mesangial cells

Stimulation of p38 Phosphorylation and Activity by Arachidonic Acid in HeLa Cells, HL60 Promyelocytic Leukemic Cells, and Human Neutrophils

Evidence that cytosolic phospholipase A₂ is down‐regulated by protein kinase C in intact human platelets stimulated with fluoroaluminate

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Phosphorylation and Activation of Cytosolic Phospholipase A2 by 38‐kDa Mitogen‐Activated Protein Kinase in Collagen‐Stimulated Human Platelets

Cited by 148 publications

References 49 publications

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H2O2and PDGF in mesangial cells

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H2O2and PDGF in mesangial cells

Stimulation of p38 Phosphorylation and Activity by Arachidonic Acid in HeLa Cells, HL60 Promyelocytic Leukemic Cells, and Human Neutrophils

Evidence that cytosolic phospholipase A2 is down‐regulated by protein kinase C in intact human platelets stimulated with fluoroaluminate

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Phosphorylation and Activation of Cytosolic Phospholipase A₂ by 38‐kDa Mitogen‐Activated Protein Kinase in Collagen‐Stimulated Human Platelets

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H₂O₂and PDGF in mesangial cells

ERK and p38 MAP kinase are involved in arachidonic acid release induced by H₂O₂and PDGF in mesangial cells

Evidence that cytosolic phospholipase A₂ is down‐regulated by protein kinase C in intact human platelets stimulated with fluoroaluminate