Vig, Eva, Melissa Green, Yuanwen Liu, Kang-Yeol Yu, Hyung-Joo Kwon, Jun Tian, Mark G. Goebl, and Maureen A. Harrington, 2001, J. Biol. Chem., 276 (11):7859-7866.
From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202-5121
The IL-1 receptor-associated kinase (IRAK/mPLK) is linked to the regulation of nuclear factor-B (NF-B)-dependent gene expression. Here we describe a novel binding partner of IRAK/mPLK that we term SIMPL (signaling molecule that associates with the mouse pelle-like kinase). Overexpression of SIMPL leads to the activation of NF-B-dependent promoters, and inactivation of SIMPL inhibits IRAK/mPLK as well as tumor necrosis factor receptor type I-induced NF-B activity. Dominant inhibitory alleles of IB kinase (IKK or IKK) block the activation of NF-B by IRAK/mPLK and SIMPL. Furthermore, SIMPL binds IRAK/mPLK and the IKKs in vitro and in vivo. In the presence of antisense mRNA to SIMPL, the physical association between IRAK/mPLK and IKK but not IRAK/mPLK and IKK is greatly diminished. Moreover, dominant-negative SIMPL blocks IKK- or IKK-induced NF-B activity. These results lead us to propose a model in which SIMPL functions to regulate NF-B activity by linking IRAK/mPLK to IKK/-containing complexes.
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