Specificities of CD40 signaling: Involvement of TRAF2 in CD40-induced NF-kappa B activation and intercellular adhesion molecule-1 up-regulation

Several tumor necrosis factor receptor-associated factor (TRAF) family prot eins including TRAF2, TRAF3, TRAF5, and TRAF6, as well as Jak3, have been i mplicated as potential mediators of CD40 signaling. An extensive in vitro b inding study indicated that TRAF2 and TRAF3 bind to the CD40 cytoplasmic ta il (CD40ct) with much higher affinity than TRAF5 and TRAF6 and that TRAF2 a nd TRAF3 bind to different residues of the CD40ct. Using CD40 mutants incap able of binding TRAF2, TRAF3, or Jak3, we found that the TRAF2-binding site of the CD40ct is critical for NF-kappa B and stress-activated protein kina se activation, as well as the up-regulation of the intercellular adhesion m olecule-1 (ICAM-1) gene, whereas binding of TRAF3 and Jak3 is dispensable f or all of these functions. Overexpression of a dominantly active I kappa B alpha strongly inhibited CD40-induced NF-kappa B activation, ICAM-1 promote r activity, and cell-surface ICAM-1 up regulation. These studies suggest a potential signal transduction pathway from the CD40 receptor to the transcr iptional activation of the ICAM-1 gene.