Interleukin-1R–Associated Kinase 2 Is a Novel Modulator of the Transforming Growth Factor β Signaling Cascade

Abstract

The transforming growth factor β (TGFβ) pathway orchestrates an extensive transcriptional program that is important for many processes in the cell. For example, TGFβ regulates cell cycle, migration, and epithelial-tomesenchymal transition. The TGFβ 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 TGFβ 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 TGFβ-responsive reporter assay. Several genes were identified that upon knockdown could repress the reporter signal; among these are the two cellular receptors for TGFβ. In addition to these two known components of the TGFβ pathway, several genes were identified that were previously not linked to the TGFβ signaling. Knockdown of one of these genes, the IRAK2 kinase, resulted not only in an impaired TGFβ 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 TGFβ-induced cell cycle arrest. Our data show that interleukin-1R-associated kinase 2 is a novel and critical component of TGFβ signaling. Mol Cancer Res; 8(4); 592-603.

The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling

“…Reverse genetic screens in mammalian cells using siRNA have been used for assessing gene function, target validation, pathway analysis, gene redundancy, and therapeutic targeting of several disorders. In an effort to elucidate novel regulators of the TGF-b pathway, siRNA library screens have identified key regulators of TGF-b signaling (34)(35)(36)(37)(38)(39)(40), although screens using TGFBRI kinase activity as a readout have not been conducted. The BTR reporter is unique in that loss of TGFBRI kinase activity results in a gain of function (increase in bioluminescence signal), and thus is less likely to result in nonspecific or off-target biological effects than are commonly observed in traditional luciferase-based screens (4).…”

Retroviral mutagenesis in a newly developed myc transgenic mouse model of human B cell and plasma cell neoplasia

“…It is well supported that IRAK2 can cause potent NF-κB activation in mice [71]. It may be that in human IRAK2 works completely independently of MyD88, in fact human IRAK2 is important during TGF-β signaling [88].…”