Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 43, Pages 35974-35982Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M506093200
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Funding
- NCI NIH HHS [CA082556, CA68485] Funding Source: Medline
- NIAID NIH HHS [AI052379, AI50213] Funding Source: Medline
- NIDDK NIH HHS [DK20593] Funding Source: Medline
- NIGMS NIH HHS [2-T32-GM07628, GM51366, GM62265] Funding Source: Medline
- NIMH NIH HHS [MH19732] Funding Source: Medline
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Transcription factor NF-kappa B plays a key regulatory role in the cellular response to pro-inflammatory cytokines such as tumor necrosis factor-alpha(TNF). In the absence of TNF, NF-kappa B is sequestered in the cytoplasm by inhibitory I kappa B proteins. Phosphorylation of I kappa B by the beta-catalytic subunit of IKK, a multicomponent I kappa B kinase, targets the inhibitor for proteolytic destruction and facilitates nuclear translocation of NF-kappa B. This pathway is initiated by TNF-dependent phosphorylation of T loop serines in IKK beta, which greatly stimulates I kappa B 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 I kappa B 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 gamma regulatory subunit. Third, deletion of the PP2A-binding site in IKK gamma attenuates T loop phosphorylation and catalytic activation of IKK beta in cells treated with TNF. Taken together, these data provide strong evidence that the formation of IKK center dot PP2A complexes is required for the proper induction of I kappa B kinase activity in vivo.
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