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

S. C. Sun, S. B. Maggirwar, E. Harhaj

Research output: Contribution to journalArticle

Abstract

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
Volume270
Issue number31
DOIs
StatePublished - 1995
Externally publishedYes

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Phosphorylation
Phosphoric Monoester Hydrolases
Chemical activation
Tumor Necrosis Factor-alpha
Degradation
Corrosion inhibitors
Protein Phosphatase 2
Okadaic Acid
Proteasome Inhibitors
T-cells
Phosphoprotein Phosphatases
Proteasome Endopeptidase Complex
Phosphotransferases
Cells
T-Lymphocytes
calyculin A

ASJC Scopus subject areas

  • Biochemistry

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Activation of NF-κB by phosphatase inhibitors involves the phosphorylation of IκBα at phosphatase 2A-sensitive sites. / Sun, S. C.; Maggirwar, S. B.; Harhaj, E.

In: Journal of Biological Chemistry, Vol. 270, No. 31, 1995, p. 18347-18351.

Research output: Contribution to journalArticle

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