SIMPL Is a Tumor Necrosis Factor-specific Regulator of Nuclear Factor-κB Activity
| Autor: | Hyung Joo Kwon, Eva Vig, Kang-Yeol Yu, Mark G. Goebl, Maureen A. Harrington, Melissa Green, Yuanwen Liu, Jun Tian |
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| Rok vydání: | 2001 |
| Předmět: |
Transcriptional Activation
medicine.medical_specialty Molecular Sequence Data Regulator Protein Serine-Threonine Kinases Biology Biochemistry Receptors Tumor Necrosis Factor Antigens CD Two-Hybrid System Techniques Interleukin-1 Receptor-Associated Kinases Internal medicine Gene expression medicine Amino Acid Sequence Receptor Molecular Biology Kinase NF-kappa B I-Kappa-B Kinase Promoter Cell Biology I-kappa B Kinase Cell biology Endocrinology Receptors Tumor Necrosis Factor Type I Calcium-Calmodulin-Dependent Protein Kinases Tumor necrosis factor alpha Protein Kinases |
| Zdroj: | Journal of Biological Chemistry. 276:7859-7866 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m010399200 |
| Popis: | The IL-1 receptor-associated kinase (IRAK/mPLK) is linked to the regulation of nuclear factor-kappaB (NF-kappaB)-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-kappaB-dependent promoters, and inactivation of SIMPL inhibits IRAK/mPLK as well as tumor necrosis factor receptor type I-induced NF-kappaB activity. Dominant inhibitory alleles of IkappaB kinase (IKKalpha or IKKbeta) block the activation of NF-kappaB 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-kappaB activity. These results lead us to propose a model in which SIMPL functions to regulate NF-kappaB activity by linking IRAK/mPLK to IKKbeta/alpha-containing complexes. |
| Databáze: | OpenAIRE |
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