Positive regulation of IκB kinase signaling by protein serine/threonine phosphatase 2A

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

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Transcription factor NF-κB plays a key regulatory role in the cellular response to pro-inflammatory cytokines such as tumor necrosis factor-α (TNF). In the absence of TNF, NF-κB is sequestered in the cytoplasm by inhibitory IκB proteins. Phosphorylation of IκB by the β-catalytic subunit of IKK, a multicomponent IκB kinase, targets the inhibitor for proteolytic destruction and facilitates nuclear translocation of NF-κB. This pathway is initiated by TNF-dependent phosphorylation of T loop serines in IKKβ, which greatly stimulates IκB 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 IκB 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 IKKγ regulatory subunit. Third, deletion of the PP2A-binding site in IKKγ attenuates T loop phosphorylation and catalytic activation of IKKβ 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 IκB kinase activity in vivo.

Original languageEnglish (US)
Pages (from-to)35974-35982
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number43
DOIs
StatePublished - Oct 28 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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