c-Jun Is a Downstream Target for Ceramide-activated Protein Phosphatase in A431 Cells

Reyes, Juan González; Robayna, Ignacio González; Delgado, Pino Santana; Gonzalez, Inmaculada Hernandez; Quintana, José; Estévez, Francisco; Fanjul, Luisa F.; Galarreta, C. M. Ruiz de

doi:10.1074/jbc.271.35.21375

Cited by 58 publications

(29 citation statements)

References 57 publications

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“…The kinetics of ceramide-induced TCR up-regulation were comparable with the kinetics of ceramide-induced activation of phosphatases (29,30), and experiments using protein phosphatase inhibitors demonstrated that the ceramide-induced TCR up-regulation most probably was mediated via ceramide-activated protein phosphatases belonging to the PP2A group. This is in agreement with previous studies demonstrating that ceramide is a potent activator of PP2A (17,18).…”

Section: Discussionmentioning

confidence: 65%

Ceramide-Induced TCR Up-Regulation

Menné

Lauritsen

Dietrich

et al. 2000

The Journal of Immunology

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The TCR is a constitutively recycling receptor meaning that a constant fraction of TCR from the plasma membrane is transported inside the cell at the same time as a constant fraction of TCR from the intracellular pool is transported to the plasma membrane. TCR recycling is affected by protein kinase C activity. Thus, an increase in protein kinase C activity affects TCR recycling kinetics leading to a new TCR equilibrium with a reduced level of TCR expressed at the T cell surface. Down-regulation of TCR expression compromises T cell activation. Conversely, TCR up-regulation is expected to increase T cell responsiveness. The purpose of this study was to identify and characterize potential pathways for TCR up-regulation. We found that ceramide affected TCR recycling dynamics and induced TCR up-regulation in a concentration- and time-dependent manner. Experiments applying phosphatase inhibitors indicated that ceramide-induced TCR up-regulation was most probably mediated by serine/threonine protein phosphatase 2A. Analyses of T cell variants demonstrated that TCR up-regulation was dependent on the presence of an intact CD3γ L-based motif and thus acted on TCR engaged in the recycling pathway. Finally, we showed that TCR up-regulation probably plays a physiological role by increasing T cell responsiveness. Thus, by affecting the TCR recycling kinetics, T cells have the potential both to up- and down-regulate TCR expression and thereby adjust T cell responsiveness.

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Section: Discussionmentioning

confidence: 65%

Ceramide-Induced TCR Up-Regulation

Menné

Lauritsen

Dietrich

et al. 2000

The Journal of Immunology

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“…Nuclear factor (erythroid-derived-2)-like 2 and PP2A signaling has been demonstrated to be elevated in 78-kD glucose-regulated protein knockout cells, possibly to counteract increased ER stressassociated ROS production (42). In addition, ceramide alters PP2A activity (43), and smoke-induced ceramide production is redox-sensitive in a neutral-sphingomyelinase manner (44). Therefore, GPx-1 could alter ceramide production and exert an impact on cellular apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction

Geraghty

Hardigan

Wallace

et al. 2013

Am J Respir Cell Mol Biol

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Protein phosphatase-2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and chronic obstructive pulmonary disease (COPD). Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase-1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B affected lung PP2A activity and airway inflammation. Experiments using gene silencing techniques in mouse lung or human small airway epithelial cells determined that knocking down PTP1B expression blocked GPx-1's activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a nonresponsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung disease. Indeed, PTP1B protein was oxidized in the lungs of subjects with advanced emphysema, and cigarette smoke did not increase GPx-1 or PTP1B activity within epithelial cells isolated from subjects with COPD, unlike samples of healthy lung epithelial cells. In conclusion, these findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung-tissue destruction in response to cigarette smoke exposure.Keywords: phosphorylation; inflammation; oxidation; kinase Protein phosphatase-2A (PP2A) is the major serine-threonine eukaryotic phosphatase (1), and accounts for up to 1% of total cellular protein (2). Altered PP2A activity plays a key role in cancer (3), neurodegenerative diseases (4), and innate immune responses (5). In the lung, PP2A is a key modulator of inflammatory responses in asthma (6) and chronic obstructive pulmonary disease (COPD) (5). Despite its importance in these and other biological processes, the mechanisms by which PP2A is regulated within the lung remains to be determined. Increasing evidence indicates that PP2A activity is sensitive to the redox status of the cell (7). Indeed, deficiencies in PP2A activity during Alzheimer disease (8) and chronic lymphocytic leukemia (9) are associated with enhanced oxidative stress and impaired antioxidant defenses (10,11). Despite the established links between oxidative stress and altered PP2A activity, the biological pathways by which redox factors modulate PP2A activity to influence disease development are not yet known.Increased oxidative injury has been detected in the lungs of patients with COPD, and animal studies demonstrate that inflammation in this disease can be regulated by the redox status of the lung (12, 13). COPD is the th...

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“…If sphingomyelinase activation is responsible for ceramide generation in a given cell system, increases in ceramide levels should parallel decreases in sphingomyelin levels (see for example Ref. 19). As shown in Fig.…”

Section: Lps/paf Stimulation Of P388d 1 Cells Elevates Intracellularmentioning

confidence: 99%

“…After the indicated times, supernatants were discarded, and the cell monolayers were scraped in 0.5 ml of 0.5% Triton X-100. Lipids were extracted according to Bligh and Dyer (16) and separated by thin-layer chromatography in the solvent system chloroform/benzene/ethanol (80:40:75, v/v/v) followed by another run in the mobile phase chloroform/methanol/28% ammonium hydroxide (65:25:5, v/v/v), as described (18,19). Lipids were visualized by exposing the plates to iodine vapors.…”

Section: Measurement Of Ceramide and Sphingomyelin Levels In [ 14 C]mentioning

confidence: 99%

Inflammatory Activation of Arachidonic Acid Signaling in Murine P388D1 Macrophages via Sphingomyelin Synthesis

Balsinde

Balboa

Dennis

1997

Journal of Biological Chemistry

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Ceramide has emerged as an important lipid messenger for many cellular processes triggered via surface receptors. In the present study, inflammatory activation of P388D 1 macrophages with bacterial lipopolysaccharide (LPS) and platelet-activating factor (PAF) stimulated a transient accumulation of ceramide. Moreover, cell-permeable ceramide mimicked LPS/PAF in triggering arachidonate mobilization in these cells. LPS/PAFinduced ceramide synthesis did not result from sphingomyelinase activation but from increased de novo synthesis. Participation of this pathway in arachidonate signaling was detected since fumonisin B 1 , an inhibitor of de novo ceramide synthesis, was able to inhibit the LPS/PAF-induced response. These studies have uncovered a new role for sphingolipid metabolism in cellular signaling and constitute evidence that products of the sphingomyelin biosynthetic pathway may serve a specific role in signal transduction by influencing the activity of the novel Group V secretory phospholipase A 2 .

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c-Jun Is a Downstream Target for Ceramide-activated Protein Phosphatase in A431 Cells

Cited by 58 publications

References 57 publications

Ceramide-Induced TCR Up-Regulation

Ceramide-Induced TCR Up-Regulation

The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction

Inflammatory Activation of Arachidonic Acid Signaling in Murine P388D1 Macrophages via Sphingomyelin Synthesis

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