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 Goebl, Maureen Harrington

Research output: Contribution to journalArticle

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

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Phosphotransferases
Interleukin-1 Receptor-Associated Kinases
Tumor Necrosis Factor-alpha
Chemical activation
Receptors, Tumor Necrosis Factor, Type I
Gene expression
Alleles
Association reactions
Gene Expression
Messenger RNA
Molecules
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry

Cite this

SIMPL Is a Tumor Necrosis Factor-specific Regulator of Nuclear Factor-κB Activity. / Vig, Eva; Green, Melissa; Liu, Yuanwen; Yu, Kang Yeol; Kwon, Hyung Joo; Tian, Jun; Goebl, Mark; Harrington, Maureen.

In: Journal of Biological Chemistry, Vol. 276, No. 11, 16.03.2001, p. 7859-7866.

Research output: Contribution to journalArticle

Vig, Eva ; Green, Melissa ; Liu, Yuanwen ; Yu, Kang Yeol ; Kwon, Hyung Joo ; Tian, Jun ; Goebl, Mark ; Harrington, Maureen. / SIMPL Is a Tumor Necrosis Factor-specific Regulator of Nuclear Factor-κB Activity. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 11. pp. 7859-7866.
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