TAK1 is an essential regulator of BMP signalling in cartilage.
TAK1 is an essential regulator of BMP signalling in cartilage.
复制标题
DOI：
10.1038/emboj.2009.162
复制
发表时间：
2009-07-22
期刊：
影响因子：
11.4
通讯作者：
Glimcher, Laurie H.
中科院分区：
文献类型：
--
作者：
Shim, Jae-Hyuck;Greenblatt, Matthew B.;Xie, Min;Schneider, Michael D.;Zou, Weiguo;Zhai, Bo;Gygi, Steven;Glimcher, Laurie H.
TGFβ激活激酶1（TAK 1）是MAPKKK家族的成员，控制从先天性和适应性免疫系统激活到血管发育和凋亡的多种功能。为了分析TAK 1在软骨中的体内功能，我们产生了由胶原蛋白2启动子驱动的Tak 1条件性缺失的小鼠。Tak 1col 2小鼠表现出严重的软骨发育不良，伴有发育迟缓、次级骨化中心形成受损以及关节异常，包括肘关节脱位和跗关节融合。这种表型类似于骨形态发生蛋白受体（BMPR）1和Gdf 5缺陷小鼠。在TAK 1缺陷的软骨细胞中，BMPR信号传导明显受损，这通过已知BMP靶基因的表达减少以及Smad 1/5/8和p38/JNK/Erk MAP激酶的磷酸化减少来证明。TAK 1介导Smad 1在C-末端丝氨酸残基的磷酸化。这些发现提供了第一个在体内的证据，在哺乳动物系统中，TAK 1是所需的BMP信号和功能作为上游激活激酶的Smad 1/5/8除了其已知的作用，在调节MAP激酶途径。我们的实验揭示了TAK 1在软骨的形态发生、生长和维持中的重要作用。
TGFβ activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1col2 mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage.
登录
查看更多内容
影响因子：
4.8
作者：
Hoffmann, A;Preobrazhenska, O;Verschueren, K
通讯作者：
Verschueren, K
影响因子：
2.8
作者：
Grimsrud, CD;Romano, PR;O'Keefe, RJ
通讯作者：
O'Keefe, RJ
影响因子：
30.5
作者：
Sato, S;Sanjo, H;Akira, S
通讯作者：
Akira, S
影响因子：
2.6
作者：
Komatsu, Y;Shibuya, H;Yamada, G
通讯作者：
Yamada, G
影响因子：
4.6
作者：
Jadrich, JL;O'Connor, MB;Coucouvanis, E
通讯作者：
Coucouvanis, E