Akt enhances Runx2 protein stability by regulating Smurf2 function during osteoblast differentiation
Akt enhances Runx2 protein stability by regulating Smurf2 function during osteoblast differentiation
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DOI：
10.1111/febs.12887
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发表时间：
2014-08-01
期刊：
影响因子：
5.4
通讯作者：
Lee, Kwang Youl
中科院分区：
文献类型：
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作者：
Choi, You Hee;Kim, Yeon-Jin;Lee, Kwang Youl
Runx2 在骨形成和软骨细胞成熟中发挥重要作用。 Akt 促进骨形态发生蛋白 BMP2 诱导的成骨细胞分化，并增强 Runx2 的功能和转录活性。然而，Runx2 和 Akt 之间关系的精确分子机制尚不清楚。在本研究中，我们研究了 Akt 在调节 Runx2 功能中的作用。我们发现 Akt 增加了 Runx2 蛋白的稳定性。然而，Runx2 mRNA 的水平不受 Akt 影响，我们没有发现任何 Akt 直接修饰 Runx2 的证据。相反，我们发现有证据表明 Akt 诱导 Smad 泛素化调节因子 Smurf2 磷酸化，并通过泛素/蛋白酶体介导的 Smurf2 降解降低 Smurf2 蛋白水平。 Akt 还可以减轻 Smurf2 介导的 Runx2 转录活性抑制。综上所述，我们的结果表明，Akt 至少部分通过调节泛素/蛋白酶体介导的 Smurf2 降解来增强 Runx2 的蛋白质稳定性和转录活性，从而调节成骨细胞分化。
Runx2 plays essential roles in bone formation and chondrocyte maturation. Akt promotes osteoblast differentiation induced by the bone morphogenetic proteins BMP2 and enhances the function and transcriptional activity of Runx2. However, the precise molecular mechanism underlying the relationship between Runx2 and Akt is not well understood. In this study, we examined the role of Akt in regulating Runx2 function. We found that Akt increases the stability of Runx2 protein. However, the level of Runx2 mRNA was not affected by Akt, and we did not find any evidence for direct modification of Runx2 by Akt. Instead, we found evidence that Akt induces the phosphorylation of the Smad ubiquitination regulatory factor Smurf2 and decreases the level of Smurf2 protein through ubiquitin/proteasome-mediated degradation of Smurf2. Akt also alleviates Smurf2-mediated suppression of Runx2 transcriptional activity. Taken together, our results suggest that Akt regulates osteoblast differentiation, at least in part, by enhancing the protein stability and transcriptional activity of Runx2 through regulation of ubiquitin/proteasome-mediated degradation of Smurf2.