Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis.
Signals emanating from the receptor for interleukin-1 (IL-1), lipopolysaccharide (LPS) or osteoclast differentiation factor/receptor activator of NF kappa B ligand (ODF/RANKL) stimulate transcription factors AP-1 through mitogen-activated protein kinase (MAPK) activation and NF kappa B through I kappa B 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 NF kappa B 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 NF kappa B. 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.
Department of Hematology, Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo 162-8655, Japan.
N
N
Kobayashi
Y
Y
Kadono
A
A
Naito
K
K
Matsumoto
T
T
Yamamoto
S
S
Tanaka
J
J
Inoue
D000818:Animals; D001665:Binding Sites; D001862:Bone Resorption / Q000378:metabolism*; D002454:Cell Differentiation; D004789:Enzyme Activation; D007375:Interleukin-1 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D016335:Zinc Fingers; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases