Regulation of stress-activated protein kinase signaling pathway by protein phosphatase 2C (PP2C)

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(1) PP2Cε precipitates in negative regulation of TAK1 and ASK1Ectopic expression of PP2Cε in mammalian cells represses the activity of TAK1 and ASK1, two mitogen-activated protein kinase kinase kinases. PP2Cε keeps these kinases in an inactive state in quiescent cells by associating with and dephosphorylating them. PP2Cε associated with TAK1 and ASK1 in quiescent cells, but the association was transiently suppressed in response to treatment of the cells with IL-1 and H_2_O_2, respectively, which activate these respective kinases. On the basis of these results we proposed that PP2Cε regulates TAK1 and ASK1 pathways by a common regulatory mechanism.(2) PP2Cδ (ILKAP) participates in positive regulation of ASK1In contrast to PP2Cε, PP2Cδ (ILKAP) acts as a positive regulator of TNF induced SAPK signaling. Transient expression of PP2Cδ (ILKAP) in 293 cells enhanced TNF induced activation of JNK and p38. PP2Cδ (ILKAP) associated with ASK1 and this association was enhanced in response to TNF treatment. These results suggested that PP2Cδ (ILKAP) may dephosphorylate inhibitory phosphorylation site(s) of ASK1.(3) JNK negatively regulates PP2CζPP2Cζ, a PP2C family member that is enriched in testicular germ cells, is phosphorylated at Ser92 and Thr202/205 by JNK but not by p38 or ERK both in vivo and in vitro. We show that phosphorylation of PP2Cζ at Ser92 but not at Thr202/205 repressed its phosphatase activity.