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

Kobayashi, Norihiko; Kadono, Yuho; Naito, Asuka; Matsumoto, Kunihiro; Yamamoto, Tadashi; Tanaka, Sakae; Inoue, Jun‐ichiro

doi:10.1093/emboj/20.6.1271

Cited by 434 publications

(360 citation statements)

References 44 publications

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“…It has become clear that RANK transduces key signals by directly interacting with TRAF6 [24,25]. In addition, it has been reported that PLCγ2 binds to Gab2 in response to RANKL, mediates Gab2 recruitment to RANK, and is required for osteoclast formation [10,20].…”

Section: Discussionmentioning

confidence: 99%

Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis

et al. 2013

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The receptor activator of NF-κB (RANK) and immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors are essential factors involved in regulating osteoclast formation and bone remodeling. Here, we identify early estrogen-induced gene 1 (EEIG1) as a novel RANK ligand (RANKL)-inducible protein that physically interacts with RANK and further associates with Gab2, PLCγ2 and Tec/Btk kinases upon RANKL stimulation. EEIG1 positively regulates RANKL-induced osteoclast formation, likely due to its ability to facilitate RANKL-stimulated PLCγ2 phosphorylation and NFATc1 induction. In addition, an inhibitory peptide designed to block RANK-EEIG1 interaction inhibited RANKL-induced bone destruction by reducing osteoclast formation. Together, our results identify EEIG1 as a novel RANK signaling component controlling RANK-mediated osteoclast formation, and suggest that targeting EEIG1 might represent a new therapeutic strategy for the treatment of pathological bone resorption.

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Section: Discussionmentioning

confidence: 99%

Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis

et al. 2013

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“…51 Functional domains of TRAF6 involved in MAPK activation have been characterized. 53 Among the various domains investigated, the RING finger and the first zinc finger domains are required for activation of TAK1 and downstream p38 and JNK MAPK 53 ( Figure 3). Moreover, TRAF6 has also been demonstrated to activate p38 and JNK MAPK during osteoclast differentiation by favoring ROS production through increased NAPDH oxidase activity 54 (Figure 3).…”

Section: The P38 Mapk Signaling Pathway In Osteoclastsmentioning

confidence: 99%

Focus on the p38 MAPK signaling pathway in bone development and maintenance

2015

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The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated in response to a wide range of extracellular signals. As a consequence, it can generate many different biological effects that depend on the stimulus and on the activated cell type. Therefore, this pathway has been found to regulate many aspects of tissue development and homeostasis. Recent work with the aid of genetically modified mice has highlighted the physiological functions of this pathway in skeletogenesis and postnatal bone maintenance. In this review, emphasis is given to the roles of the p38 MAPK pathway in chondrocyte, osteoblast and osteoclast biology. In particular, we describe the molecular mechanisms of p38 MAPK activation and downstream targets. The requirement of this pathway in physiological bone development and homeostasis is demonstrated by the ability of p38 MAPK to regulate master transcription factors controlling geneses and functions of chondrocytes, osteoblasts and osteoclasts.

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“…COS7 cells were cultured in DMEM supplemented with 10% FCS and antibiotics (complete DMEM). Wild-type (WT) murine embryonic fibroblast (MEF), TRAF6-deficient (TRAF6 Ϫ/Ϫ ) MEF (20), and Plat-E cells (21) were established and maintained as described elsewhere.…”

Section: Cell Culturementioning

confidence: 99%

“…It has been reported that TRAF6 is involved in the signaling pathways of IL-1-and IL-17-induced NF-B activation (20,25,26). To determine whether TRAF6 is involved in IL-25R-mediated signaling, we investigated the effect of a DN TRAF6 on IL-25R-mediated NF-B activation.…”

Section: Traf6 Is Crucial For Il-25r-mediated Nf-b Activationmentioning

confidence: 99%

Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling

Maezawa

Nakajima

Suzuki

et al. 2006

The Journal of Immunology

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IL-25 (IL-17E) induces IL-4, IL-5, and IL-13 production from an unidentified non-T/non-B cell population and subsequently induces Th2-type immune responses such as IgE production and eosinophilic airway inflammation. IL-25R is a single transmembrane protein with homology to IL-17R, but the IL-25R signaling pathways have not been fully understood. In this study, we investigated the signaling pathway under IL-25R, especially the possible involvement of TNFR-associated factor (TRAF)6 in this pathway. We found that IL-25R cross-linking induced NF-κB activation as well as ERK, JNK, and p38 activation. We also found that IL-25R-mediated NF-κB activation was inhibited by the expression of dominant negative TRAF6 but not of dominant negative TRAF2. Furthermore, IL-25R-mediated NF-κB activation, but not MAPK activation, was diminished in TRAF6-deficient murine embryonic fibroblast. In addition, coimmunoprecipitation assay revealed that TRAF6, but not TRAF2, associated with IL-25R even in the absence of ligand binding. Finally, we found that IL-25R-mediated gene expression of IL-6, TGF-β, G-CSF, and thymus and activation-regulated chemokine was diminished in TRAF6-deficient murine embryonic fibroblast. Taken together, these results indicate that TRAF6 plays a critical role in IL-25R-mediated NF-κB activation and gene expression.

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

Cited by 434 publications

References 44 publications

Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis

Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis

Focus on the p38 MAPK signaling pathway in bone development and maintenance

Involvement of TNF Receptor-Associated Factor 6 in IL-25 Receptor Signaling

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