Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation.
Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation.
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DOI：
10.1016/j.bbrc.2015.06.105
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发表时间：
2015-08
影响因子：
3.1
通讯作者：
E. Sumiya;Takako Negishi-Koga;Y. Nagai;Ayako Suematsu;T. Suda;M. Shinohara;Kojiro Sato;H. Sanjo;S. Akira;H. Takayanagi
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文献类型：
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作者：
E. Sumiya;Takako Negishi-Koga;Y. Nagai;Ayako Suematsu;T. Suda;M. Shinohara;Kojiro Sato;H. Sanjo;S. Akira;H. Takayanagi
TAK1（由map3k7编码）是一种丝裂原活化蛋白激酶激酶（MAP3K），在NF-κB配体受体激活因子（receptor activator of NF-κB ligand， RANKL）刺激下激活转录因子AP-1和NF-κB，是破骨细胞分化的关键调控因子。在这里，我们报道了TAK1激酶活性在活体ctsk - cre小鼠和TAK1突变小鼠的破骨细胞分化晚期的功能相关性，其中TAK1激酶结构域两侧是loxP。由于破骨细胞数量的显著减少，ap3k7flox/kdCtskCre/+小鼠表现出严重的骨质疏松表型。rankl诱导的MAPK和NF-κB的激活在破骨细胞分化的后期受损。给药的NF-κB抑制剂对晚期破骨细胞形成没有抑制作用，因此我们研究了破骨细胞分化中未知的TAK1靶点。我们对来自mmap3k7flox /kdCtskCre/+小鼠的rankl刺激的破骨细胞前体细胞进行了磷酸化蛋白质组学分析，揭示了TAK1在破骨细胞发生过程中调节的多个靶点。因此，TAK1作为控制破骨细胞发生的各种细胞蛋白的磷酸化状态的关键调节器。
TAK1 (encoded byMap3k7) is a mitogen-activated protein kinase kinase kinase (MAP3K), which activates the transcription factors AP-1 and NF-κB in response to receptor activator of NF-κB ligand (RANKL) stimulation, thus constituting a key regulator of osteoclast differentiation. Here we report the functional relevance of the kinase activity of TAK1 in the late stage of osteoclast differentiationin vivousingCtsk-Cre mice and TAK1 mutant mice in which the TAK1 kinase domain was flanked by loxP. TheMap3k7flox/kdCtskCre/+mice displayed a severe osteopetrotic phenotype due to a marked decrease in osteoclast number. RANKL-induced activation of MAPK and NF-κB was impaired in the late stage of osteoclast differentiation. The absence of suppressive effect of an administered NF-κB inhibitor on the late stage of osteoclastogenesis led us to investigate unknown TAK1 targets in osteoclast differentiation. We performed a phosphoproteomic analysis of RANKL-stimulated osteoclast precursor cells fromMap3k7flox/kdCtskCre/+mice, revealing multiple targets regulated by TAK1 during osteoclastogenesis. Thus, TAK1 functions as a critical regulator of the phosophorylation status of various cellular proteins that govern osteoclastogenesis.