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Originally published In Press as doi:10.1074/jbc.M010399200 on November 28, 2000

J. Biol. Chem., Vol. 276, Issue 11, 7859-7866, March 16, 2001
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SIMPL Is a Tumor Necrosis Factor-specific Regulator of Nuclear Factor-kappa B Activity*

Eva Vig, Melissa Green, Yuanwen Liu, Kang-Yeol Yu, Hyung-Joo Kwon, Jun Tian, Mark G. Goebl, and Maureen A. HarringtonDagger

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-kappa B (NF-kappa 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-kappa B-dependent promoters, and inactivation of SIMPL inhibits IRAK/mPLK as well as tumor necrosis factor receptor type I-induced NF-kappa B activity. Dominant inhibitory alleles of Ikappa B kinase (IKKalpha or IKKbeta ) block the activation of NF-kappa 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 IKKbeta but not IRAK/mPLK and IKKalpha is greatly diminished. Moreover, dominant-negative SIMPL blocks IKKalpha - or IKKbeta -induced NF-kappa B activity. These results lead us to propose a model in which SIMPL functions to regulate NF-kappa B activity by linking IRAK/mPLK to IKKbeta /alpha -containing complexes.

* This work was supported by National Institutes of Health Grant AI42798 (to M. A. H.) and National Science Foundation Grant 9728069 (to M. G. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF093135.

Dagger To whom correspondence should be addressed. Tel.: 317-274-7527; Fax: 317-274-7592; E-mail: mharrin@iupui.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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