Activation of NF-κB by RANK Requires Tumor Necrosis Factor Receptor-associated Factor (TRAF) 6 and NF-κB-inducing Kinase IDENTIFICATION OF A NOVEL TRAF6 INTERACTION MOTIF

摘要: Various members of the tumor necrosis factor (TNF) receptor superfamily activate nuclear κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways through their interaction with TNF receptor-associated factors (TRAFs) NF-κB-inducing (NIK). We have previously shown that cytoplasmic domain activator NF-κB (RANK) interacts TRAF2, TRAF5, TRAF6 its overexpression activates JNK pathways. Through a detailed mutational analysis RANK, we demonstrate TRAF2 TRAF5 bind to consensus TRAF binding motifs located in C terminus at positions 565–568 606–611, respectively. In contrast, novel motif between residues 340 358 RANK. Furthermore, transfection experiments RANK deletion mutants human embryonic 293 cells revealed TRAF6-binding region (340–358), but not or TRAF5-binding region, is necessary sufficient for RANK-induced activation. Moreover, mutant NIK (NIK-KM) inhibited However, RANK-mediated activation required distal portion (427–603) containing TRAF2-binding domain. Thus, our results indicate various TRAFs distinct via motif, which then NIK, thus leading activation, whereas most likely TRAF2-interacting