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J. Biol. Chem., Vol. 280, Issue 43, 35974-35982, October 28, 2005

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Positive Regulation of IB Kinase Signaling by Protein Serine/Threonine Phosphatase 2A^*

Arlene E. Kray1, Robert S. Carter, Kevin N. Pennington, Rey J. Gomez, Laura E. Sanders, Joan M. Llanes, Wasif N. Khan, Dean W. Ballard, and Brian E. Wadzinski2

From the Department of Pharmacology and the Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232

Transcription factor NF-B plays a key regulatory role in the cellular response to pro-inflammatory cytokines such as tumor necrosis factor- (TNF). In the absence of TNF, NF-B is sequestered in the cytoplasm by inhibitory IB proteins. Phosphorylation of IBby the -catalytic subunit of IKK, a multicomponent IB kinase, targets the inhibitor for proteolytic destruction and facilitates nuclear translocation of NF-B. This pathway is initiated by TNF-dependent phosphorylation of T loop serines in IKK, which greatly stimulates IB kinase activity. Prior in vitro mixing experiments indicate that protein serine/threonine phosphatase 2A (PP2A) can dephosphorylate these T loop serines and inactivate IKK, suggesting a negative regulatory role for PP2A in IKK signaling. Here we provided several in vivo lines of evidence indicating that PP2A plays a positive rather than a negative role in the regulation of IKK. First, TNF-induced degradation of IB is attenuated in cells treated with okadaic acid or fostriecin, two potent inhibitors of PP2A. Second, PP2A forms stable complexes with IKK in untransfected mammalian cells. This interaction is critically dependent on amino acid residues 121–179 of the IKK regulatory subunit. Third, deletion of the PP2A-binding site in IKK attenuates T loop phosphorylation and catalytic activation of IKK in cells treated with TNF. Taken together, these data provide strong evidence that the formation of IKK·PP2A complexes is required for the proper induction of IB kinase activity in vivo.

Received for publication, June 3, 2005 , and in revised form, August 12, 2005.

^* This work was supported in part by National Institutes of Health Grants GM51366, GM62265 (to B. E. W.), CA082556, AI052379 (to D. W. B.), and AI50213 (to W. N. K.), the Vanderbilt Diabetes Research and Training Center Grant DK20593, the Vanderbilt-Ingram Cancer Center Grant CA68485, the Center for Molecular Neurosciences Grant MH19732, and by American Cancer Society Grant RSG TBE-102299 (to W. N. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by National Institutes of Health Predoctoral Training Grant 2-T32-GM07628.

² To whom correspondence should be addressed: Vanderbilt University Medical Center, Dept. of Pharmacology, 424 RRB, Nashville, TN 37232-6600. Tel.: 615-343-2080; Fax: 615-343-6532; E-mail: brian.wadzinski{at}vanderbilt.edu.

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