PPM1A and PPM1B act as IKK beta phosphatases to terminate TNF alpha-induced IKK beta-NF-kappa B activation

IKK beta serves as a central intermediate signaling molecule in the activation of the NF-kappa B pathway. However, the precise mechanism for the termination of IKK beta activity is still not fully understood. Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, PPM1A and PPM1B, as IKK beta phosphatases. Overexpression of PPM1A or PPM1B results in dephosphorylation of IKK beta at Ser177 and Ser181 and termination of IKK beta-induced NF-kappa B activation. PPM1A and PPM1B associate with the phosphorylated form of IKK beta, and the interaction between PPM1A/PPM1B and IKK beta is induced by TNF alpha in a transient fashion in the cells. Furthermore, knockdown of PPM1A and PPM1B expression enhances TNF alpha-induced IKK beta phosphorylation, NF-kappa B nuclear translocation and NF-kappa B-dependent gene expression. These data suggest that PPM1A and PPM1B play an important role in the termination of TNF alpha-mediated NF-kappa B activation through dephosphorylating and inactivating IKK beta. (C) 2008 Elsevier Inc. All rights reserved.