Functional role of c-Src in IL-1-induced NF-κB activation: c-Src is a component of the IKK complex

Megumi Funakoshi-Tago, Kenji Tago, Kumi Andoh, Yoshiko Sonoda, Shin Ichi Tominaga, Tadashi Kasahara

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Interleukin-1 (IL-1) mediates numerous host responses through the rapid activation of nuclear factor-κB (NF-κB), but the signal pathways leading to NF-κB activation are regulated at multiple stages. Here, we propose a novel regulatory system for IL-1-induced NF-κB activation by a tyrosine kinase, c-Src. The kinase activity of c-Src increases in an IL-1-dependent manner and the ectopic expression of c-Src augments IL-1-induced NF-κB activation, suggesting the involvement of c-Src in IL-1 signaling. However, a Src family inhibitor, PP2 failed to inhibit IL-1-induced NF-κB activation, and the expression of a c-Src mutant lacking kinase activity (c-Src KD) augmented IL-1-induced NF-κB activation as well as wild type c-Src, indicating that the tyrosine kinase activity is not required for IL-1-induced NF-κB activation. Furthermore, a physiological interaction between c-Src and Iκc;B kinase γ (IKKγ) was observed, implying the involvement of c-Src in the IKK-complex. While c-Src augmented IL-1-induced IKK activation independent of its kinase activity, the region comprising amino acids 361-440 in the c-Src kinase domain are required for NF-κB; activation. The same region of c-Src is also required for IL-1-induced IKK activation and the association with IKKγ. Taken together, our results suggest that c-Src plays a critical role in IL-1-induced NF-κB activation through the IKK complex.

Original languageEnglish
Pages (from-to)189-197
Number of pages9
JournalJournal of biochemistry
Volume137
Issue number2
DOIs
Publication statusPublished - 2005 Feb 1

Keywords

  • IKKγ
  • IL-1-induced NF-κB activation
  • IκB-Complex
  • c-Src
  • c-Src KD

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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