ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction.

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the MAPKKK family in the JNK and p38 mitogen-activated protein kinase cascades and critically involved in stress- and cytokine-induced apoptosis. The transcription factor nuclear factor-kappaB (NF-kappaB) is a pivotal regulator of immune and inflammatory responses and exerts anti-apoptotic roles in various ...
cells. Here we show that ASK1 directly interacts with transforming growth factor-beta-activated kinase 1 (TAK1), another MAPKKK that has been identified as a signaling intermediate in the interleukin 1 (IL-1)-induced NF-kappaB pathway as well as the transforming growth factor-beta superfamily-induced JNK/p38 pathway. Overexpression of ASK1 inhibits IL-1-, TRAF6-, or TAK1-induced, but not NF-kappaB-inducing kinase-induced, NF-kappaB activation. ASK1 dissociates TAK1 but not NF-kappaB-inducing kinase from TRAF6. Moreover, IL-1-induced complex formation of endogenous TAK1 and TRAF6 was blocked by ASK1 overexpression. It thus appears that the inhibition of NF-kappaB by ASK1 may result at least in part from the disruption of the TRAF6.TAK1 complex formation in the IL-1 signaling pathway. These results provide a new insight in the mode of action of MAPKKK family members; two distinct MAPKKKs in the same MAP kinase cascades directly interact and exert opposite effects in another signaling pathway, NF-kappaB.
Mesh Terms:
Cell Line, Humans, Interleukin-1, JNK Mitogen-Activated Protein Kinases, Kinetics, MAP Kinase Kinase Kinase 5, MAP Kinase Kinase Kinases, Mitogen-Activated Protein Kinases, NF-kappa B, Proteins, Receptors, Interleukin-1, Receptors, Interleukin-1 Type I, Recombinant Proteins, Signal Transduction, TNF Receptor-Associated Factor 6, Transfection, p38 Mitogen-Activated Protein Kinases
J. Biol. Chem.
Date: Oct. 20, 2000
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