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Molecular and Cellular Biology, February 2002, p. 992-1000, Vol. 22, No. 4
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.4.992-1000.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Receptor Activator of NF-{kappa}B Ligand (RANKL) Activates TAK1 Mitogen-Activated Protein Kinase Kinase Kinase through a Signaling Complex Containing RANK, TAB2, and TRAF6

Junko Mizukami,1 Giichi Takaesu,2 Hiroyuki Akatsuka,1 Hiroaki Sakurai,1 Jun Ninomiya-Tsuji,2 Kunihiro Matsumoto,2 and Naoki Sakurai1*

Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Yodogawa-ku, Osaka 532-8505,1 Department of Molecular Biology, Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya 464-8602, Japan2

Received 16 July 2001/ Returned for modification 21 August 2001/ Accepted 20 November 2001

The receptor activator of NF-{kappa}B (RANK) and its ligand RANKL are key molecules for differentiation and activation of osteoclasts. RANKL stimulates transcription factors AP-1 through mitogen-activated protein kinase (MAPK) activation, and NF-{kappa}B through I{kappa}B kinase (IKK) activation. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is essential for activation of these kinases. In the interleukin-1 signaling pathway, TAK1 MAPK kinase kinase (MAPKKK) mediates MAPK and IKK activation via interaction with TRAF6, and TAB2 acts as an adapter linking TAK1 and TRAF6. Here, we demonstrate that TAK1 and TAB2 participate in the RANK signaling pathway. Dominant negative forms of TAK1 and TAB2 inhibit NF-{kappa}B activation induced by overexpression of RANK. In 293 cells stably transfected with full-length RANK, RANKL stimulation facilitates the formation of a complex containing RANK, TRAF6, TAB2, and TAK1, leading to the activation of TAK1. Furthermore, in murine monocyte RAW 264.7 cells, dominant negative forms of TAK1 and TAB2 inhibit NF-{kappa}B activation induced by RANKL and endogenous TAK1 is activated in response to RANKL stimulation. These results suggest that the formation of the TRAF6-TAB2-TAK1 complex is involved in the RANK signaling pathway and may regulate the development and function of osteoclasts.

* Corresponding author. Present address: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-50 Kawagishi 2-chome, Toda, Saitama 335-8505, Japan. Phone: 81-48-433-8068. Fax: 81-48-433-8159. E-mail: nsakurai{at}tanabe.co.jp.

Molecular and Cellular Biology, February 2002, p. 992-1000, Vol. 22, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.4.992-1000.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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