TAO2 Directs TAK1 to JNK

Abstract

Transforming growth factor β-activated kinase 1 (TAK1) is capable of stimulating both the c-Jun N-terminal kinase (JNK) pathway and the nuclear factor κB (NF-κB) pathway. HuangFu et al . show that in response to osmotic stress, TAK1 selectively activates JNK without activating NF-κB. After validating that osmotic stress or interleukin-1 (IL-1) both activated TAK1 in cultured 293 IL-1R1 cells (stably expressing the IL-1 receptor), the authors showed that only IL-1 stimulated both JNK phosphorylation and the DNA binding activity of NF-κB and degradation of inhibitor of NF-κB (IκB). TAK1-deficient cells that expressed a truncated form of TAK1 lacking the kinase domain (TAK1Δ/Δ) failed to activate JNK in response to osmotic stress, confirming the importance of the kinase activity of TAK1 in the response. A yeast two-hybrid screen identified TAO1 (thousand-and-one amino acid kinase 1) as a binding partner for TAK1, and coimmunoprecipitation experiments confirmed that both TAO1 and the related protein TAO2, which is known to participate in JNK signaling, interacted with TAK1. The interaction did not require the kinase activity of TAO2, because a catalytically inactive mutant of TAO2 also bound TAK1. Overexpression of activated TAK1 can stimulate NF-κB activity; however, when activated TAK1 and TAO2 or the catalytically inactive form of TAO2 were coexpressed, NF-κB activation was diminished. In contrast, coexpression of activated TAK1 and TAO2 augmented JNK activation. Overexpression of TAO2 also inhibited NF-κB activation in response to tumor necrosis factor (TNF), which is also mediated by TAK1. TAO2 did not interfere with kinase activity of TAK1; instead, TAO2 interfered with the interaction between TAK1 and IKK (IκB kinase), which is required for degradation of IκB and activation of NF-κB. Knockdown of TAO2 using RNA interference resulted in decreased JNK activation and a modest activation of NF-κB in response to osmotic stress. Thus, TAO2 has a kinase-independent function in controlling the signaling pathways activated by TAK1, thus allowing the cell to use the same kinase TAK1 to mediate different responses to different stimuli. W.-C. HuangFu, E. Omori, S. Akira, K. Matsumoto, J. Ninomiya-Tsuji, Osmotic stress activates the TAK1-JNK pathway while blocking TAK1-mediated NF-κB activation: TAO2 regulates TAK1 pathways. J. Biol. Chem. 281 , 28802-28810 (2006). [Abstract] [Full Text]