Activation of NF-κB by phosphatase inhibitors involves the phosphorylation of IκBα at phosphatase 2A-sensitive sites

Shao Cong Sun, Sanjay B. Maggirwar, Edward Harhaj

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Activation of NF-κB by various cellular stimuli involves the phosphorylation and subsequent degradation of its inhibitor, IκBα, although the underlying mechanism remains unclear. In the present study, the role of serine/threonine phosphatases in the regulation of IκBα phosphorylation was investigated. Our studies demonstrate that incubation of human T cells with low concentrations (~ 1-5 nM) of calyculin A or okadaic acid, potent inhibitors of protein phosphatase type 1 (PP-1) and type 2A (PP-2A), induces the phosphorylation of IκBα even in the absence of any cellular stimulus. This action of the phosphatase inhibitors, which is associated with the activation of the RelA·p50 NF-κB heterodimer, is not affected by agents that block the induction of IκBα phosphorylation by tumor necrosis factor alpha (TNF-α). Furthermore, the phosphorylated IκBα from calyculin A- treated cells, but not that from TNF-α-stimulated cells, is sensitive to PP- 2A in vitro, suggesting the existence of fundamental differences in the phosphorylation of IκBα induced by the two different NF-κB inducers. However, induction of IκBα phosphorylation by both TNF-α and the phosphatase inhibitors is associated with the subsequent degradation of IκBα. We further demonstrate that TNF-α- and calyculin A-induced IκBα degradation exhibits similar but not identical sensitivities to a proteasome inhibitor. Together, these results suggest that phosphorylation of IκBα, mediated through both the TNF-α-inducible and the PP-2A-opposing kinases, may serve to target IκBα for proteasome-mediated degradation.

Original languageEnglish (US)
Pages (from-to)18347-18351
Number of pages5
JournalJournal of Biological Chemistry
Issue number31
StatePublished - Aug 4 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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