Interleukin-1R-associated kinase 2 is a novel modulator of the transforming growth factor beta signaling cascade

The transforming growth factor beta (TGFbeta) pathway orchestrates an extensive transcriptional program that is important for many processes in the cell. For example, TGFbeta regulates cell cycle, migration, and epithelial-to-mesenchymal transition. The TGFbeta pathway has a dual role in cancer: it...

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Bibliographic Details
Published in:Molecular cancer research Vol. 8; no. 4; p. 592
Main Authors: Mullenders, Jasper, Fabius, Armida W M, van Dongen, Miranda M W, Kuiken, Hendrik J, Beijersbergen, Roderick L, Bernards, René
Format: Journal Article
Language:English
Published: United States 01.04.2010
Subjects:
Active Transport, Cell Nucleus - genetics
Cell Line, Tumor
Down-Regulation - genetics
Gene Expression Regulation, Neoplastic - genetics
Genes, cdc - physiology
Genetic Testing
Humans
Interleukin-1 Receptor-Associated Kinases - genetics
Interleukin-1 Receptor-Associated Kinases - metabolism
Neoplasm Invasiveness - genetics
RNA, Small Interfering - genetics
Signal Transduction - genetics
Smad2 Protein - genetics
Smad2 Protein - metabolism
Transforming Growth Factor beta - genetics
ISSN:1557-3125, 1557-3125
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Summary:The transforming growth factor beta (TGFbeta) pathway orchestrates an extensive transcriptional program that is important for many processes in the cell. For example, TGFbeta regulates cell cycle, migration, and epithelial-to-mesenchymal transition. The TGFbeta pathway has a dual role in cancer: it is involved in early-stage tumor suppression but also contributes to tumor progression by promoting invasion. To identify the novel genes involved in TGFbeta pathway signaling, we have performed a functional genetic loss-of-function screen. We screened a small interfering RNA library targeting 700 kinases and kinase-related genes in a TGFbeta-responsive reporter assay. Several genes were identified that upon knockdown could repress the reporter signal; among these are the two cellular receptors for TGFbeta. In addition to these two known components of the TGFbeta pathway, several genes were identified that were previously not linked to the TGFbeta signaling. Knockdown of one of these genes, the IRAK2 kinase, resulted not only in an impaired TGFbeta target gene response but also in a reduction of the nuclear accumulation and phosphorylation of SMAD2. In addition, suppression of interleukin-1R-associated kinase 2 expression led to a partial override of a TGFbeta-induced cell cycle arrest. Our data show that interleukin-1R-associated kinase 2 is a novel and critical component of TGFbeta signaling.
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ISSN:1557-3125
1557-3125
DOI:10.1158/1541-7786.MCR-09-0386