Involvement of Regulatory and Catalytic Subunits of Phosphoinositide 3-Kinase in NF-κ B Activation

Hypoxia, reoxygenation, and the tyrosine phosphatase inhibitor pervanadate activate the transcription factor NF-κ B involving phosphorylation of its inhibitor Iκ B-α on tyrosine 42. This modification does not lead to degradation of Iκ B by the proteasome/ubiquitin pathway, as is seen on stimulation...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-01, Vol.96 (2), p.429-434
Main Authors: Beraud, Christophe, Henzel, William J., Baeuerle, Patrick A.
Format: Article
Language:English
Subjects:
Antibodies
Biological Sciences
Goods and services tax
Phosphatidylinositols
Phosphorylation
Proteins
Reporter genes
T lymphocytes
Transcription factors
Transfection
Western blotting
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Summary:Hypoxia, reoxygenation, and the tyrosine phosphatase inhibitor pervanadate activate the transcription factor NF-κ B involving phosphorylation of its inhibitor Iκ B-α on tyrosine 42. This modification does not lead to degradation of Iκ B by the proteasome/ubiquitin pathway, as is seen on stimulation of cells with proinflammatory cytokines. It is currently unknown how tyrosine-phosphorylated Iκ B is removed from NF-κ B. Here we show that p85α, the regulatory subunit of PI3-kinase, specifically associates through its Src homology 2 domains with tyrosine-phosphorylated Iκ B-α in vitro and in vivo after stimulation of T cells with pervanadate. This association could provide a mechanism by which newly tyrosine-phosphorylated Iκ B is sequestered from NF-κ B. Another mechanism by which PI3-kinase contributed to NF-κ B activation in response to pervanadate appeared to involve its catalytic p110 subunit. This was evident from the inhibition of pervanadate-induced NF-κ B 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-κ B activities. Wortmannin did not inhibit tyrosine phosphorylation of Iκ B-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-κ B activation by the tyrosine phosphorylation-dependent pathway.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.2.429