ROLE OF TAK1 IN RANKL SIGNALING PATHWAY

TAK1 在 RANKL 信号通路中的作用

• 批准号: 6929234
• 负责人: Jun Ninomiya-Tsuji
• 金额: $ 14.41万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929234
• 关键词: JUN kinase; L cell; biological signal transduction; cell differentiation; cell growth regulation; electrophoresis; immunoprecipitation; intermolecular interaction; mitogen activated protein kinase; molecular cloning; osteoclasts; osteogenesis; osteoprotegerin; protein structure function; receptor binding; transcription factor; transfection /expression vector

DESCRIPTION (provided by applicant): Bone integrity is maintained through the coordinated action of bone resorption by osteoclasts and bone formation by osteoblasts. RANKL (receptor activator of nuclear factor kappaB (NF-kappaB) ligand) is a key factor for differentiation and activation of osteoclasts. Chronic inflammation and cancer metastasis to bone induce excessive bone resorption primarily by enhancing production of RANKL. RANKL binds to its receptor RANK (receptor activator of NF-kappaB) and initiates intercellular signaling by recruiting intercellular adaptor TRAF6 (tumor necrosis factor receptor-associated factor 6). RANKL/RANK/TRAF6-mediated signaling leads to activation of transcription factor NF-kappaB, mitogen-activated kinases JNK and p38, oncogene product c-Src and transcription factor c-Fos expression, which are important for osteoclastogenesis. However, the link between RANK/TRAF6 and the downstream effectors has not been identified. We have previously demonstrated that TAK1 (transforming growth factor beta activated kinase), a member of MAPKKK (mitogen-activated kinase kinase kinase), plays essential roles in proinflammatory signaling and cell differentiation. Recently, we have found that RANKL induces endogenous association of TAK1 and TAB2 (TAK1 binding protein 2) with RANK/TRAF6. Therefore, we hypothesize that TAK1 and TAB2 also play essential roles in RANKL signaling pathway. In this exploratory/developmental proposal, we will determine the roles of TAK1/TAB2 in RANKL-dependent signaling pathways and obtain data to develop in vivo model to further verify the specific roles of TAK1/TAB2 in osteoclastogenesis. Our specific Aims are: 1) To determine the roles of TAK1/TAB2 in RANKL-induced NF-kappaB, JNK, p38 and c-Src activation, c-Fos induction and osteoclastogenesis: 2) To design and create mutant TAK1 and TAB2 proteins that lack the ability to transmit the RANKL-dependent signaling but are intact in mediating other signaling pathways. We will plan to use those mutants to demonstrate functional roles of the RANK/TRAF6/TAB2/TAK1 signaling in osteoclastogenesis in the future study. These studies will advance the understanding of the molecular mechanisms underlying the osteoclastogenesis and may offer novel therapeutic targets for bone diseases caused by excessive osteoclastogenesis.

描述（由申请人提供）：通过破骨细胞的骨吸收和成骨细胞的骨形成的协调作用来维持骨完整性。RANKL （receptor activator of nuclear factor kappaB, NF-kappaB）配体)是破骨细胞分化和活化的关键因子。慢性炎症和骨癌转移主要通过增强RANKL的产生来诱导过度骨吸收。RANKL与其受体RANK （NF-kappaB受体激活因子）结合，并通过募集细胞间接头TRAF6（肿瘤坏死因子受体相关因子6）启动细胞间信号传导。RANKL/RANK/ traf6介导的信号传导可激活转录因子NF-kappaB、丝裂原活化激酶JNK和p38、癌基因产物c-Src和转录因子c-Fos的表达，这些对破骨细胞的发生至关重要。然而，RANK/TRAF6与下游效应物之间的联系尚未确定。TAK1（转化生长因子β活化激酶）是MAPKKK（丝裂原活化激酶激酶）的一个成员，在促炎信号传导和细胞分化中起重要作用。最近，我们发现RANKL诱导TAK1和TAB2 （TAK1结合蛋白2）与RANK/TRAF6的内源性关联。因此，我们假设TAK1和TAB2也在RANKL信号通路中发挥重要作用。在这个探索性/发展性的建议中，我们将确定TAK1/TAB2在rankl依赖的信号通路中的作用，并获得数据来开发体内模型，以进一步验证TAK1/TAB2在破骨细胞发生中的具体作用。我们的具体目标是：1)确定TAK1/TAB2在rankl诱导的NF-kappaB、JNK、p38和c-Src激活、c-Fos诱导和破骨细胞发生中的作用；2)设计和创建缺乏传递rankl依赖性信号通路能力但在介导其他信号通路中完好无损的突变TAK1和TAB2蛋白。我们计划在未来的研究中使用这些突变体来证明RANK/TRAF6/TAB2/TAK1信号在破骨细胞发生中的功能作用。这些研究将促进对破骨细胞发生的分子机制的理解，并可能为过度破骨细胞发生引起的骨病提供新的治疗靶点。

项目成果

Osmotic stress blocks NF-kappaB-dependent inflammatory responses by inhibiting ubiquitination of IkappaB.

渗透压通过抑制 IkappaB 泛素化来阻断 NF-kappaB 依赖性炎症反应。

• DOI: 10.1016/j.febslet.2007.11.002
• 发表时间: 2007
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: HuangFu,Wei-Chun;Matsumoto,Kunihiro;Ninomiya-Tsuji,Jun
• 通讯作者: Ninomiya-Tsuji,Jun

TAK1 is a component of the Epstein-Barr virus LMP1 complex and is essential for activation of JNK but not of NF-kappaB.

TAK1 是 Epstein-Barr 病毒 LMP1 复合物的组成部分，对于 JNK 的激活至关重要，但对于 NF-kappaB 的激活则不然。

• DOI: 10.1074/jbc.m509834200
• 发表时间: 2006
• 期刊: The Journal of biological chemistry
• 作者: Uemura,Noriyuki;Kajino,Taisuke;Sanjo,Hideki;Sato,Shintaro;Akira,Shizuo;Matsumoto,Kunihiro;Ninomiya-Tsuji,Jun
• 通讯作者: Ninomiya-Tsuji,Jun

TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis

• DOI: 10.1074/jbc.m603384200
• 发表时间: 2006-07-14
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Omori, Emily;Matsumoto, Kunihiro;Ninomiya-Tsuji, Jun
• 通讯作者: Ninomiya-Tsuji, Jun