SIMPL Is a Tumor Necrosis Factor-specific Regulator of Nuclear Factor-κB Activity

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

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Abstract

The IL-1 receptor-associated kinase (IRAK/mPLK) is linked to the regulation of nuclear factor-κB (NF-κB)-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-κB-dependent promoters, and inactivation of SIMPL inhibits IRAK/mPLK as well as tumor necrosis factor receptor type I-induced NF-κB activity. Dominant inhibitory alleles of IκB kinase (IKKα or IKKβ) block the activation of NF-κB 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 IKKβ but not IRAK/mPLK and IKKα is greatly diminished. Moreover, dominant-negative SIMPL blocks IKKα- or IKKβ-induced NF-κB activity. These results lead us to propose a model in which SIMPL functions to regulate NF-κB activity by linking IRAK/mPLK to IKKβ/ α-containing complexes.

Original languageEnglish (US)
Pages (from-to)7859-7866
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number11
DOIs
StatePublished - Mar 16 2001

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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