NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.

The activation of NF-kappaB by receptors in the tumor necrosis factor (TNF) receptor and Toll/interleukin-1 (IL-1) receptor families requires the TRAF family of adaptor proteins. Receptor oligomerization causes the recruitment of TRAFs to the receptor complex, followed by the activation of a kinase cascade that results in the phosphorylation of ...
IkappaB. TANK is a TRAF-binding protein that can inhibit the binding of TRAFs to receptor tails and can also inhibit NF-kappaB activation by these receptors. However, TANK also displays the ability to stimulate TRAF-mediated NF-kappaB activation. In this report, we investigate the mechanism of the stimulatory activity of TANK. We find that TANK interacts with TBK1 (TANK-binding kinase 1), a novel IKK-related kinase that can activate NF-kappaB in a kinase-dependent manner. TBK1, TANK and TRAF2 can form a ternary complex, and complex formation appears to be required for TBK1 activity. Kinase-inactive TBK1 inhibits TANK-mediated NF-kappaB activation but does not block the activation mediated by TNF-alpha, IL-1 or CD40. The TBK1-TANK-TRAF2 signaling complex functions upstream of NIK and the IKK complex and represents an alternative to the receptor signaling complex for TRAF-mediated activation of NF-kappaB.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Antigens, CD40, CD40 Ligand, Cell Line, Dose-Response Relationship, Drug, Enzyme Activation, Humans, Interleukin-1, JNK Mitogen-Activated Protein Kinases, Membrane Glycoproteins, Mitogen-Activated Protein Kinases, Molecular Sequence Data, NF-kappa B, Protein-Serine-Threonine Kinases, Proteins, Sequence Homology, Amino Acid, Signal Transduction, TNF Receptor-Associated Factor 2, Tumor Necrosis Factor-alpha, Two-Hybrid System Techniques
EMBO J.
Date: Dec. 01, 1999
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