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

  • Christophe Béraud
  • William J. Henzel
  • Patrick A. Baeuerle
The National Academy of Sciences
Publication Date
Jan 19, 1999


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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