© 2005 The Japanese Biochemical Society
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Functional Role of c-Src in IL-1–Induced NF-
B Activation: c-Src Is a Component of the IKK Complex
1 Department of Biochemistry and Immunology, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512; and 2 Department of Biochemistry, Jichi Medical School, 3311-1 Minamikawachi-machi, Tochigi
3 To whom correspondence should be addressed. Tel/Fax: +81-3-5400-2697, E-mail: kasahara-td{at}kyoritsu-ph.ac.jp
Interleukin-1 (IL-1) mediates numerous host responses through the rapid activation of nuclear factor-
B (NF-B), but the signal pathways leading to NF-B activation are regulated at multiple stages. Here, we propose a novel regulatory system for IL-1–induced NF-B 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-B activation, suggesting the involvement of c-Src in IL-1 signaling. However, a Src family inhibitor, PP2 failed to inhibit IL-1–induced NF-B activation, and the expression of a c-Src mutant lacking kinase activity (c-Src KD) augmented IL-1–induced NF-B activation as well as wild type c-Src, indicating that the tyrosine kinase activity is not required for IL-1–induced NF-B activation. Furthermore, a physiological interaction between c-Src and IB kinase 
(IKK) 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-B activation. The same region of c-Src is also required for IL-1–induced IKK activation and the association with IKK. Taken together, our results suggest that c-Src plays a critical role in IL-1–induced NF-B activation through the IKK complex.
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