THE HUMAN TOLL SIGNALING PATHWAY - DIVERGENCE OF NUCLEAR FACTOR KAPPA-B AND JNK SAPK ACTIVATION UPSTREAM OF TUMOR-NECROSIS-FACTOR RECEPTOR-ASSOCIATED FACTOR-6 (TRAF6)/

The human homologue of Drosophila Toll (hToll) is a recently cloned re ceptor of the interleukin 1 receptor (IL-IR) superfamily, and has been implicated in the activation of adaptive immunity. Signaling by hToll is shown to occur through sequential recruitment of the adapter molec ule MyD88 and the IL-1R-associated kinase. Tumor necrosis factor recep tor-activated factor 6 (TRAF6) and the nuclear factor kappa B (NF-kapp a B)-inducing kinase (NIK) are both involved in subsequent steps of NF -kappa B activation. Conversely, a dominant negative version of TRAF6 failed to block hToll-induced activation of stress-activated protein k inase/c-Jun NH2-terminal kinases, thus suggesting an early divergence of the two pathways.