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  • The EMBO Journal (2001) 20, 1271 - 1280
  • doi:10.1093/emboj/20.6.1271

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

Norihiko Kobayashi1,6, Yuho Kadono2,6, Asuka Naito3, Kunihiro Matsumoto4, Tadashi Yamamoto3, Sakae Tanaka2 and Jun-ichiro Inoue5

  1. Department of Hematology, Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo 162-8655, Japan
  2. Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
  3. Division of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
  4. Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-01, Japan
  5. Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Kanagawa 223-8522, Japan
  6. N.Kobayashi and Y.Kadono contributed equally to this work

Correspondence to:

Jun-ichiro Inoue, E-mail: jinoue@applc.keio.ac.jp

Received 9 November 2000; Accepted 24 January 2001; Revised 22 January 2001

Signals emanating from the receptor for interleukin-1 (IL-1), lipopolysaccharide (LPS) or osteoclast differentiation factor/receptor activator of NFkappaB ligand (ODF/RANKL) stimulate transcription factors AP-1 through mitogen-activated protein kinase (MAPK) activation and NFkappaB through IkappaB 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 NFkappaB 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 NFkappaB. 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.

  • Keywords:

    • MAPK,
    • NFkappaB,
    • osteoclastogenesis,
    • RANK,
    • TRAF