PPM1A and PPM1B act as IKKβ phosphatases to terminate TNFα-induced IKKβ-NF-κB activation

Abstract

IKKβ serves as a central intermediate signaling molecule in the activation of the NF-κB pathway. However, the precise mechanism for the termination of IKKβ activity is still not fully understood. Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, PPM1A and PPM1B, as IKKβ phosphatases. Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKβ at Ser177 and Ser181 and termination of IKKβ-induced NF-κB activation. PPM1A and PPM1B associate with the phosphorylated form of IKKβ, and the interaction between PPM1A/PPM1B and IKKβ is induced by TNFα in a transient fashion in the cells. Furthermore, knockdown of PPM1A and PPM1B expression enhances TNFα-induced IKKβ phosphorylation, NF-κB nuclear translocation and NF-κB-dependent gene expression. These data suggest that PPM1A and PPM1B play an important role in the termination of TNFα-mediated NF-κB activation through dephosphorylating and inactivating IKKβ.

Dopamine D2 Receptor Relies upon PPM/PP2C Protein Phosphatases to Dephosphorylate Huntingtin Protein

“…have been reported to share common substrates (31,32). Therefore, we resolved to individually knocking them down in HEK cells.…”

Mg2+/Mn2+-Dependent Phosphatase 1A Is Involved in Regulating Pregnane X Receptor–Mediated Cytochrome p450 3A4 Gene Expression

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The GAS41-PP2Cβ Complex Dephosphorylates p53 at Serine 366 and Regulates Its Stability

“…On the one hand, PP2C␤ suppresses a cell survival signal derived from the NFB signaling pathway and activates a proapoptotic signal by dephosphorylating the pro-apoptotic protein, BAD. Therefore, PP2C␤ seems to facilitate growth arrest and cell death through multiple targets and mechanisms (28,29). On the other hand, PP2C␤ is a negative regulator of stress signaling pathways that include the p38 and c-Jun pathways (30).…”