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Papers In Press, published online ahead of print November 29, 2004
J. Biol. Chem, 10.1074/jbc.M409718200
Submitted on August 24, 2004
Revised on November 22, 2004
Accepted on November 29, 2004

Protein phosphatase 2A regulates apoptosis in neutrophils by dephosphorylating both p38 MAPK and its substrate caspase 3

Maria Alvarado-Kristensson and Tommy Andersson

Department of Experimental Pathology, Lund University, Malmö SE20502

Corresponding Author: Maria.Alvarado-kristensson{at}exppat.mas.lu.se

Induction of apoptosis in neutrophils is an essential event in resolution of an inflammatory process. We recently found that 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. Pharmacological inhibition of this phosphatase during Fas-induced apoptosis augmented the levels of phosphorylation of both p38 MAPK and caspase 3, resulting in decreased activity of caspase 3 and increased neutrophil survival. The complementary finding of a time-dependent association between PP2A, p38 MAPK, and caspase 3 in intact neutrophils indicated that there is a direct regulatory link between 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 not only impaired the p38 MAPK-mediated inhibition of caspase 3, but it also restored the activity to caspase 3 that had already been phosphorylated and thereby inactivated. These findings indicate that PP2A plays a pivoting, dual role in the induction of neutrophil apoptosis and therefore also in the resolution of inflammation.


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