Protein phosphatase 2A regulates apoptosis in neutrophils by dephosphorylating both p38 MAPK and its substrate caspase 3.
The induction of apoptosis in neutrophils is an essential event in the resolution of an inflammatory process. We found recently that the reduction of the activity of the neutrophil survival factor p38 MAPK and dephosphorylation and thus activation of caspases must occur to initiate such cell death in these leukocytes. Here, we report a previously undetected early and transient activation of protein phosphatase 2A (PP2A) in neutrophils undergoing apoptosis. The pharmacological inhibition of this phosphatase during Fas-induced apoptosis augmented the levels of phosphorylation of both p38 MAPK and caspase 3, resulting in a decreased activity of caspase 3 and an increased neutrophil survival. The complementary finding of a time-dependent association among PP2A, p38 MAPK, and caspase 3 in intact neutrophils indicated that there is a direct regulatory link among these signaling enzymes during Fas-provoked apoptosis. Moreover, immunoprecipitated active p38 MAPK and recombinant phosphorylated caspase 3 were dephosphorylated by exposure to purified PP2A in vitro. Consequently, the early and temporary activation of PP2A in neutrophils impaired not only the p38 MAPK-mediated inhibition of caspase 3 but also restored the activity to caspase 3 that had already been phosphorylated and thereby inactivated. These findings indicate that PP2A plays a pivotal dual role in the induction of neutrophil apoptosis and therefore also in the resolution of inflammation.
Alvarado-Kristensson
Maria
M
Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Entrance 78, 3rd Fl., SE-205 02 Malmö, Sweden. maria.alvarado-kristensson@exppat.mas.lu.se
Andersson
Tommy
T
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D009504:Neutrophils / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D012694:Serine / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D019014:fas Receptor; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases