SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity.
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.
Vig
E
E
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202-5121, USA.
Green
M
M
Liu
Y
Y
Yu
K Y
KY
Kwon
H J
HJ
Tian
J
J
Goebl
M G
MG
Harrington
M A
MA
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000502:physiology*; D051550:I-kappa B Kinase; D053592:Interleukin-1 Receptor-Associated Kinases; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011494:Protein Kinases / Q000032:analysis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D015703:Antigens, CD; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D017871:Calcium-Calmodulin-Dependent Protein Kinases