Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation
Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation
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DOI：
10.1016/j.cell.2005.01.035
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发表时间：
2005-04-08
期刊：
影响因子：
64.5
通讯作者：
Zhang, YE
中科院分区：
文献类型：
--
作者：
Yamashita, M;Ying, SX;Zhang, YE
骨在整个生命过程中通过破骨细胞和成骨细胞的协调作用不断吸收和形成。在这里，我们表明，Smurf 1，HECT结构域泛素连接酶，具有特定的生理作用，抑制成骨细胞的成骨活性。Smurf 1缺陷小鼠出生正常，但表现出年龄依赖性的骨量增加。这种增加的原因可以追溯到成骨细胞的活性增强，在没有Smurf 1的情况下，成骨细胞对骨形态发生蛋白（BMP）变得敏感。然而，Smurf 1的缺失并不影响典型的Smad介导的细胞内TGF β或BMP信号传导;相反，它会导致磷酸化MEKK 2的积累和下游JNK信号级联的激活。我们证明了Smurf 1与MEKK 2的物理相互作用，并促进MEKK 2的泛素化和营业额。这些结果表明，Smurf 1通过控制MEKK 2降解来负调节成骨细胞活性和对BMP的反应。
Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced activities of osteoblasts, which become sensitized to bone morphogenesis protein (BMP) in the absence of Smurf1. However, loss of Smurf1 does not affect the canonical Smad-mediated intracellular TGF beta or BMP signaling; instead, it leads to accumulation of phosphorylated MEKK2 and activation of the downstream JNK signaling cascade. We demonstrate that Smurf1 physically interacts with MEKK2 and promotes the ubiquitination and turnover of MEKK2. These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation.