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

doi:10.1093/emboj/18.23.6694

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18 (23): 6694-6704

NF- $kappa$ B activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase

Joel L. Pomerantz and David Baltimore

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
¹ Corresponding author
e-mail: baltimo{at}caltech.edu

The activation of NF- $kappa$ B by receptors in the tumor necrosis factor (TNF) receptor and Toll/interleukin-1 (IL-1) receptor familiesrequires the TRAF family of adaptor proteins. Receptor oligomerizationcauses the recruitment of TRAFs to the receptor complex, followedby the activation of a kinase cascade that results in the phosphorylationof I $kappa$ B. TANK is a TRAF-binding protein that can inhibit the bindingof TRAFs to receptor tails and can also inhibit NF- $kappa$ B activationby these receptors. However, TANK also displays the ability tostimulate TRAF-mediated NF- $kappa$ B activation. In this report, we investigatethe mechanism of the stimulatory activity of TANK. We find thatTANK interacts with TBK1 (TANK-binding kinase 1), a novel IKK-relatedkinase that can activate NF- $kappa$ B in a kinase-dependent manner. TBK1,TANK and TRAF2 can form a ternary complex, and complex formationappears to be required for TBK1 activity. Kinase-inactive TBK1inhibits TANK-mediated NF- $kappa$ B activation but does not block theactivation mediated by TNF- $alpha$ , IL-1 or CD40. The TBK1-TANK-TRAF2signaling complex functions upstream of NIK and the IKK complexand represents an alternative to the receptor signaling complexfor TRAF-mediated activation of NF- $kappa$ B.