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

AUTOR(ES)

Kobayashi, Norihiko

FONTE

Oxford University Press

RESUMO

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.

Documentos Relacionados

• RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis
• Helicobacter pylori CagA activates NF-κB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination
• Discrete Functions of TRAF1 and TRAF2 in Drosophila melanogaster Mediated by c-Jun N-Terminal Kinase and NF-κB-Dependent Signaling Pathways
• T6BP, a TRAF6-interacting protein involved in IL-1 signaling
• Molecular basis for CD40 signaling mediated by TRAF3