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Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-κB activation

Authors
  • Christophe Béraud
  • William J. Henzel
  • Patrick A. Baeuerle
Publisher
The National Academy of Sciences
Publication Date
Jan 19, 1999
Source
PMC
Keywords
License
Unknown

Abstract

Hypoxia, reoxygenation, and the tyrosine phosphatase inhibitor pervanadate activate the transcription factor NF-κB, involving phosphorylation of its inhibitor IκB-α on tyrosine 42. This modification does not lead to degradation of IκB by the proteasome/ubiquitin pathway, as is seen on stimulation of cells with proinflammatory cytokines. It is currently unknown how tyrosine-phosphorylated IκB is removed from NF-κB. Here we show that p85α, the regulatory subunit of PI3-kinase, specifically associates through its Src homology 2 domains with tyrosine-phosphorylated IκB-α in vitro and in vivo after stimulation of T cells with pervanadate. This association could provide a mechanism by which newly tyrosine-phosphorylated IκB is sequestered from NF-κB. Another mechanism by which PI3-kinase contributed to NF-κB activation in response to pervanadate appeared to involve its catalytic p110 subunit. This was evident from the inhibition of pervanadate-induced NF-κB activation and reporter gene induction by treatment of cells with nanomolar amounts of the PI3-kinase inhibitor wortmannin. The compound had virtually no effect on tumor necrosis factor- and interleukin-1-induced NF-κB activities. Wortmannin did not inhibit tyrosine phosphorylation of IκB-α or alter the stability of the PI3-kinase complex but inhibited Akt kinase activation in response to pervanadate. Our data suggest that both the regulatory and the catalytic subunit of PI3-kinase play a role in NF-κB activation by the tyrosine phosphorylation-dependent pathway.

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