Characterization of the intracellular domain of receptor activator of NF-κB (RANK) -: Interaction with tumor necrosis factor receptor-associated factors and activation of NF-κB and c-Jun N-terminal kinase

被引:354
作者
Darnay, BG
Haridas, V
Ni, J
Moore, PA
Aggarwal, BB
机构
[1] Univ Texas, MD Anderson Cancer Ctr, Dept Mol Oncol, Cytokine Res Lab, Houston, TX 77030 USA
[2] Human Genome Sci Inc, Rockville, MD 20850 USA
关键词
D O I
10.1074/jbc.273.32.20551
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Various members of the tumor necrosis factor (TNF) receptor superfamily interact directly with signaling molecules of the TNF receptor-associated factor (TRAF) family to activate nuclear factor kappa B (NF-kappa B) and the c-Jun N-terminal kinase (JNK) pathway. The receptor activator of NF-kappa B (RANK), a recently described TNF receptor family member, and its ligand, RANKL, promote survival of dendritic cells and differentiation of osteoclasts. RANK contains 383 amino acids in its intracellular domain (residues 234-616), which contain three putative TRAF-binding domains (termed I, II, and III). In this study, we set out to identify the region of RANK needed for interaction with TRAF molecules and for stimulation of NF-kappa B and JNK activity. We constructed epitope-tagged RANK (F-RANK616) and three C-terminal truncations, F-RANK330, F-RANK427, and F-RANK530, lacking 85, 188, and 285 amino acids, respectively. From this deletion analysis, we determined that TRAF2, TRAF6, and TRAF6 interact with RANK at its C-terminal 85-amino acid tail; the binding affinity appeared to be in the order of TRAF2 > TRAF5 > TRAF6, Furthermore, overexpression of RANK stimulated JNK and NF-kappa B activation. When the C-terminal tail, which is necessary for TRAF binding, was deleted, the truncated RANK receptor was still capable of stimulating JNK activity but not NF-kappa B, suggesting that interaction with TRAFs is necessary for NF-kappa B activation but not necessary for activation of the JNK pathway.
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页码:20551 / 20555
页数:5
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