Kim H H, Lee D E, Shin J N, Lee Y S, Jeon Y M, Chung C H, Ni J, Kwon B S, Lee Z H
Department of Microbiology and Immunology, Chosun University Dental School, Kwangju, South Korea.
FEBS Lett. 1999 Jan 29;443(3):297-302. doi: 10.1016/s0014-5793(98)01731-1.
Receptor activator of NF-kappaB (RANK) is a recently cloned member of the tumor necrosis factor receptor (TNFR) superfamily, and its function has been implicated in osteoclast differentiation and dendritic cell survival. Many of the TNFR family receptors recruit various members of the TNF receptor-associated factor (TRAF) family for transduction of their signals to NF-kappaB and c-Jun N-terminal kinase. In this study, the involvement of TRAF family members and the activation of the JNK pathway in signal transduction by RANK were investigated. TRAF1, 2, 3, 5, and 6 were found to bind RANK in vitro. Association of RANK with each of these TRAF proteins was also detected in vivo. Expression of RANK in cultured cells also induced the activation of JNK, which was blocked by a dominant-negative form of JNK. Furthermore, by employing various C-terminal deletion mutants of RANK, the regions responsible for TRAF interaction and JNK activation were identified. TRAF5 was determined to bind to the C-terminal 11 amino acids and the other TRAF members to a region N-terminal to the TRAF5 binding site. The domain responsible for JNK activation was localized to the same region where TRAF1, 2, 3, and 6 bound, which suggests that these TRAF molecules might mediate the RANK-induced JNK activation.
核因子κB受体激活蛋白（RANK）是肿瘤坏死因子受体（TNFR）超家族中最近克隆出的成员，其功能与破骨细胞分化和树突状细胞存活有关。许多TNFR家族受体招募肿瘤坏死因子受体相关因子（TRAF）家族的各种成员，以将其信号转导至核因子κB和c-Jun氨基末端激酶。在本研究中，研究了TRAF家族成员的参与情况以及RANK信号转导中JNK途径的激活。发现TRAF1、2、3、5和6在体外与RANK结合。在体内也检测到RANK与这些TRAF蛋白中的每一种的结合。RANK在培养细胞中的表达也诱导了JNK的激活，这被JNK的显性负性形式所阻断。此外，通过使用RANK的各种C末端缺失突变体，确定了负责TRAF相互作用和JNK激活的区域。确定TRAF5与C末端的11个氨基酸结合，而其他TRAF成员与TRAF5结合位点N末端的区域结合。负责JNK激活的结构域定位于TRAF1、2、3和6结合的同一区域，这表明这些TRAF分子可能介导RANK诱导的JNK激活。
