Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis

• Published in: The EMBO journal Vol. 20; no. 6; pp. 1271 - 1280
• Main Authors: Kobayashi, Norihiko, Kadono, Yuho, Naito, Asuka, Matsumoto, Kunihiro, Yamamoto, Tadashi, Tanaka, Sakae, Inoue, Jun-ichiro
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 15.03.2001; Nature Publishing Group UK; Springer Nature B.V; Oxford University Press
• Subjects: Animals; Binding Sites; Bone Resorption - metabolism; Cell Differentiation; Enzyme Activation; Interleukin-1 - pharmacology; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides - pharmacology; MAPK; Mice; Mice, Mutant Strains; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - metabolism; NFκB; osteoclastogenesis; Osteoclasts - cytology; Osteoclasts - metabolism; p38 Mitogen-Activated Protein Kinases; Protein Binding; Protein Structure, Tertiary; Proteins - genetics; Proteins - metabolism; RANK; RANKL protein; RING finger domain; RING finger protein; Signal Transduction; TNF Receptor-Associated Factor 2; TNF Receptor-Associated Factor 5; TNF Receptor-Associated Factor 6; TRAF; TRAF6 protein; tumor necrosis factor receptor-associated factor 6; Zinc Fingers; RANK; NFκB; TRAF; MAPK; osteoclastogenesis
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1093/emboj/20.6.1271

Signals emanating from the receptor for interleukin‐1 (IL‐1), lipopolysaccharide (LPS) or osteoclast differentiation factor/receptor activator of NFκB ligand (ODF/RANKL) stimulate transcription factors AP‐1 through mitogen‐activated protein kinase (MAPK) activation and NFκB through IκB kinase (IKK) activation. These kinases are thought to be activated by tumor necrosis factor receptor‐associated factor 6 (TRAF6). However, molecular mechanisms by which TRAF6 activates various downstream kinases remain to be elucidated. We identified functional domains of TRAF6 under physiological conditions established by appropriate expression of TRAF6 mutants in TRAF6‐deficient cells. In IL‐1 and LPS signaling pathways, the RING finger and first zinc finger domains are not required for NFκB activation but are required for full activation of MAPK. However, IL‐1 and LPS signals utilize distinct regions within the zinc finger domains of TRAF6 to activate NFκB. Furthermore, the RING finger domain is not required for differentiation of splenocytes to multinuclear osteoclasts, but is essential for osteoclast maturation. Thus, TRAF6 plays essential roles in both the differentiation and maturation of osteoclasts by activating various kinases via its multiple domains.