Transforming growth factor-β-activated kinase-1 (TAK1), a MAP3K, interacts with Smad proteins and interferes with osteogenesis in murine mesenchymal progenitors
Transforming growth factor-β-activated kinase-1 (TAK1), a MAP3K, interacts with Smad proteins and interferes with osteogenesis in murine mesenchymal progenitors
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DOI：
10.1074/jbc.m503368200
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发表时间：
2005-07-22
影响因子：
4.8
通讯作者：
Verschueren, K
中科院分区：
文献类型：
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作者：
Hoffmann, A;Preobrazhenska, O;Verschueren, K
TAK 1（转化生长因子-β-活化激酶-1），一种与Raf-1和MEKK-1具有相当大的序列相似性的MAP 3 K，已被鉴定为MAPK途径的转化生长因子-β/骨形态发生蛋白（BMP）活化的胞质组分。在这项调查中，TAK 1和Smad蛋白之间的分子相互作用的特点，以及它们对BMP介导的间充质细胞分化沿着成骨/软骨形成途径的影响。在免疫共沉淀中，我们发现了TAK 1与所有测试的Smads，R-Smads Smads 1 -5，co-Smad Smads 4和抑制性Smads（I-Smad 6和I-Smad 7）的相互作用。Smad与TAK 1的相互作用通过其MH 2结构域发生。这种相互作用依赖于TAK 1中活性激酶结构域的存在。TAK 1在报告基因检测中显著干扰R-Smad反式激活，并影响Smad蛋白的亚细胞分布。活化的TAK 1还干扰了小鼠间充质祖细胞（C3 H10 T1/2）中BMP依赖性成骨发育。对于这些细胞，可以排除潜在的TAK 1介导的凋亡过程。TAK 1对BMP介导的Smad信号传导的协同和干扰影响先前已被报道。我们认为，TAK 1是一个因素，是在成骨发育过程中BMP的影响微调。
TAK1 (transforming growth factor-beta-activated kinase-1), a MAP3K with considerable sequence similarity to Raf-1 and MEKK-1, has been identified as a transforming growth factor-beta/bone morphogenetic protein (BMP)-activated cytosolic component of the MAPK pathways. In this investigation, the molecular interactions between TAK1 and Smad proteins were characterized as well as their influence on BMP-mediated mesenchymal cell differentiation along the osteogenic/chondrogenic pathway. In co-immunoprecipitations we found an interaction of TAK1 with all Smads tested, R-Smads Smads1-5, the co-Smad Smad4, and the inhibitory Smads (I-Smad6 and I-Smad7). Smad interaction with TAK1 takes place through their MH2 domain. This interaction is dependent on the presence of an active kinase domain in TAK1. TAK1 dramatically interferes with R-Smad transactivation in reporter assays and affects subcellular distribution of Smad proteins. Activated TAK1 also interferes with BMP-dependent osteogenic development in murine mesenchymal progenitor cells (C3H10T1/2). A potential TAK1-mediated apoptosis process could be excluded for these cells. Both synergistic and interfering influences of TAK1 on BMP-mediated Smad-signaling have been reported previously. We suggest that TAK1 is a factor that is involved in the fine-tuning of BMP effects during osteogenic development.