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Cell Signal. 2009 Jan;21(1):95-102. doi: 10.1016/j.cellsig.2008.09.012. Epub 2008 Oct 1.

PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation.

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Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, United States.


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

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