The serine/threonine phosphatase, PP2A: endogenous regulator of inflammatory cell signaling.
We have investigated the regulation of kinases and phosphatases in early gene activation in monocytes because these cells are implicated in the pathogenesis of acute inflammatory states, such as sepsis and acute lung injury. One early gene up-regulated by endotoxin is c-Jun, a member of the activating protein (AP) family. C-Jun is phosphorylated by c-Jun N-terminal kinase (JNK) and associates with c-Fos to form the AP-1 transcriptional activation complex that can drive cytokine expression. Inhibition of the serine/threonine phosphatase, PP2-A, with okadaic acid resulted in a significant increase in JNK activity. This finding was associated with increased phosphorylation of c-Jun, AP-1 transcriptional activity, and IL-1beta expression. Activation of PP2A inhibited JNK activity and JNK coprecipitated with the regulatory subunit, PP2A-Aalpha, supporting the conclusion that PP2A is a key regulator of JNK in the context of an inflammatory stimulus.
Shanley
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Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, OH 45229, USA. shant0@chmcc.org
Vasi
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Denenberg
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Wong
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D011232:Chemical Precipitation; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D007948:Leukemia, Monocytic, Acute; D008070:Lipopolysaccharides / Q000633:toxicity; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D019319:Okadaic Acid / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D010712:Phosphatidic Acids; D018808:Transcription Factor AP-1; C037657:dioleoylphosphatidic acid; D019319:Okadaic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases