Elucidation of molecular mechanisms of osteoclastogenesis for developing drugs that inhibit bone resorption

阐明破骨细胞生成的分子机制，用于开发抑制骨吸收的药物

• 批准号: 18390409
• 负责人: INOUE Jun-ichiro
• 金额: $ 11.28万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390409/
• 关键词: signal transduction; development & differentiation; bone metabolism; drug discovery; bone metastasis; rheumatoid arthritis; osteoporosis

TRAF6 is essential for osteoclastogenesis and plays a crucial role in both RANK- and CD40-mediated activation of IKK and MAPKs in osteoclast progenitor cells. Despite the requirement for IKK and MAPKs activation in osteoclastogenesis, RANK, but not CD40, can promote osteoclastogenesis because only RANK can induce long-term activation of the co-stimulatory signals mediated by immunoglobulin-like receptors/ITAM-containing adaptors complexes, which are required for induction of NFATcl, a master gene in osteoclastogenesis. Our previous data suggested that RANK, but not CD40, harbors a unique domain that functions in concert with the TRAF6-binding site to activate the co-stimulatory signals in a sustainable way and promote osteoclastogenesis. We identify such a functional protein domain, HCR, that is highly conserved in RANKs from various vertebrates and is essential for long-term activation of co-stimulatory signals. Addition of the HCR to the cytoplasmic tail of CD40 renders CD40 capable of inducing sustained activation of co-stimulatory signals and subsequent activation of NFATcl. Furthermore, the HCR dramatically enhances internalization of HCR-harboring receptors upon stimulation. These results suggest that the HCR can continuously link the RANK-TRAF6 axis to sustained co-stimulatory signaling pathways through control of the membrane trafficking of receptors and that the HCR may be a novel therapeutic target for pathological bone resorption.

TRAF6 对于破骨细胞生成至关重要，并且在破骨细胞祖细胞中 RANK 和 CD40 介导的 IKK 和 MAPK 激活中发挥着至关重要的作用。尽管破骨细胞生成需要 IKK 和 MAPK 激活，但 RANK（而不是 CD40）可以促进破骨细胞生成，因为只有 RANK 可以诱导由免疫球蛋白样受体/含有 ITAM 的接头复合物介导的共刺激信号的长期激活，这是诱导破骨细胞生成中的主基因 NFATcl 所必需的。我们之前的数据表明，RANK（而非 CD40）拥有一个独特的结构域，该结构域与 TRAF6 结合位点协同作用，以可持续的方式激活共刺激信号并促进破骨细胞生成。我们鉴定了这样一个功能蛋白结构域 HCR，它在来自各种脊椎动物的 RANK 中高度保守，并且对于共刺激信号的长期激活至关重要。将HCR添加至CD40的细胞质尾使得CD40能够诱导共刺激信号的持续激活以及随后的NFATc1激活。此外，HCR 在受到刺激后可显着增强 HCR 受体的内化。这些结果表明，HCR 可以通过控制受体的膜运输，将 RANK-TRAF6 轴与持续的共刺激信号通路持续连接，并且 HCR 可能是病理性骨吸收的新治疗靶点。

项目成果

Molecular mechanisms and physiological roles of the TRAF signal-mediated NF-kB activation

TRAF信号介导的NF-kB激活的分子机制和生理作用

• 发表时间: 2007
• 作者: Qin;J.;Gohda J;Maezawa Y;Sharma RK;Ito H;Yamamoto T;Maezawa Y;Sharma RK;Ito H;Yamamoto T;Maezawa Y;Sharma RK;Ito H;Yamamoto T;井上純一郎;Jun-ichiro Inoue
• 通讯作者: Jun-ichiro Inoue

Phospho-proteomics analysis of EGFR signal cascades in a non-small cell cancer cell line expressing mutated EGFR

表达突变 EGFR 的非小细胞癌细胞系中 EGFR 信号级联的磷酸化蛋白质组学分析

• 发表时间: 2007
• 作者: 松村隆之;井上純一郎;茂木秀彦;山崎孔輔;山口憲孝;尾山大明;宮坂隆
• 通讯作者: 宮坂隆

Characterization of breast cancer cells with constitutively activated NFkB

具有组成型激活的 NFkB 的乳腺癌细胞的表征

• 发表时间: 2007
• 作者: 山口憲孝;仙波憲太郎;井上純一郎
• 通讯作者: 井上純一郎

Interaction of antiproliferative protein Tob with the CCR4-NOT deadenylase complex

• DOI: 10.1111/j.1349-7006.2008.00746.x
• 发表时间: 2008-04-01
• 期刊: CANCER SCIENCE
• 影响因子: 5.7
• 作者: Miyasaka, Takashi;Morita, Masahiro;Yamamoto, Tadashi
• 通讯作者: Yamamoto, Tadashi

HTLV-1 tax-induced NFκB activation is independent of Lys-63-linked-type polyubiquitination

• DOI: 10.1016/j.bbrc.2007.03.125
• 发表时间: 2007-05-25
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Gohda, Jin;Irisawa, Masato;Inoue, Jun-ichiro
• 通讯作者: Inoue, Jun-ichiro