Insulin receptor substrate-3, interacting with Bcl-3, enhances p50 NF-kappaB activity.
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.
Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Tomohiro
T
Kabuta
Fumihiko
F
Hakuno
Yoshitake
Y
Cho
Daisuke
D
Yamanaka
Kazuhiro
K
Chida
Tomoichiro
T
Asano
Keiji
K
Wada
Shin-Ichiro
S
Takahashi
D000818:Animals; D017209:Apoptosis; D000081242:B-Cell Lymphoma 3 Protein; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D055504:Insulin Receptor Substrate Proteins; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha