Protein Phosphatase 4 Is Involved in Tumor Necrosis Factor-α-induced Activation of c-Jun N-terminal Kinase

Protein phosphatase 4 (PP4, previously named protein phosphatase X (PPX)), a PP2A-related serine/threonine phosphatase, has been shown to be involved in essential cellular processes, such as microtubule growth and nuclear factor κB activation. We provide evidence that PP4 is involved in tumor necrosis factor (TNF)-α signaling in human embryonic kidney 293T (HEK293T) cells. Treatment of HEK293T cells with TNF-α resulted in time-dependent activation of endogenous PP4, peaking at 10 min, as well as increased serine and threonine phosphorylation of PP4. We also found that PP4 is involved in relaying the TNF-α signal to c-Jun N-terminal kinase (JNK) as indicated by the ability of PP4-RL, a dominant-negative PP4 mutant, to block TNF-α-induced JNK activation. Moreover, the response of JNK to TNF-α was inhibited in HEK293 cells stably expressing PP4-RL in comparison to parental HEK293 cells. The involvement of PP4 in JNK signaling was further demonstrated by the specific activation of JNK, but not p38 and ERK2, by PP4 in transient transfection assays. However, no direct PP4-JNK interaction was detected, suggesting that PP4 exerts its positive regulatory effect on JNK in an indirect manner. Taken together, these data indicate that PP4 is a signaling component of the JNK cascade and involved in relaying the TNF-α signal to the JNK pathway.