The insulin receptor substrate (IRS) proteins are major substrates of both insulin receptor and insulin-like growth factor (IGF)-I receptor tyrosine kinases. Previously, we reported that IRS-3 is localized to both cytosol and nucleus, and possesses transcriptional activity. In the present study, we identified Bcl-3 as a novel binding protein to IRS-3. Bcl-3 is a nuclear protein, which forms a complex with the homodimer of p50 NF-kappaB, leading to enhancement of transcription through p50 NF-kappaB. We found that Bcl-3 interacts with the pleckstrin homology domain and the phosphotyrosine binding domain of IRS-3, and that IRS-3 interacts with the ankyrin repeat domain of Bcl-3. In addition, IRS-3 augmented the binding activity of p50 to the NF-kappaB DNA binding site, as well as the tumor necrosis factor (TNF)-alpha-induced transcriptional activity of NF-kappaB. Lastly, IRS-3 enhanced NF-kappaB-dependent anti-apoptotic gene induction and consequently inhibited TNF-alpha-induced cell death. This series of results proposes a novel function for IRS-3 as a transcriptional regulator in TNF-alpha signaling, distinct from its function as a substrate of insulin/IGF receptor kinases.
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