Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth
Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth
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DOI：
10.1073/pnas.1400737111
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发表时间：
2014-09-09
影响因子：
11.1
通讯作者：
Kawabe, Hiroshi
中科院分区：
文献类型：
--
作者：
Hsia, Hung-En;Kumar, Rohit;Kawabe, Hiroshi
蛋白质泛素化是神经发育的核心调控决定因素。以前的研究表明，Nedd 4家族E3泛素连接酶Nedd 4 -1和Nedd 4 -2可以泛素化磷酸酶和张力蛋白同源物（PTEN），从而调节神经元轴突生长。使用条件性基因敲除小鼠，我们在这里表明，Nedd 4 -1和Nedd 4 -2确实需要在小鼠中枢神经系统神经元轴突生长。然而，与先前发表的数据相反，我们证明了PTEN不是Nedd 4 -1和Nedd 4 -2的底物，并且在Nedd 4 -1和Nedd 4 -2缺失后，异常的PTEN泛素化不参与受损的轴突生长。相反，PTEN通过调节mTORC 1（一种控制蛋白质合成和细胞生长的蛋白质复合物）的活性来限制Nedd 4 -1蛋白水平。我们的数据表明，Nedd 4-家族E3连接酶促进轴突生长和分支在发育中的哺乳动物大脑，其中PTEN是不是一个相关的底物。相反，PTEN通过调节Nedd 4 -1的表达来控制神经突的生长。
Protein ubiquitination is a core regulatory determinant of neural development. Previous studies have indicated that the Nedd4-family E3 ubiquitin ligases Nedd4-1 and Nedd4-2 may ubiquitinate phosphatase and tensin homolog (PTEN) and thereby regulate axonal growth in neurons. Using conditional knockout mice, we show here that Nedd4-1 and Nedd4-2 are indeed required for axonal growth in murine central nervous system neurons. However, in contrast to previously published data, we demonstrate that PTEN is not a substrate of Nedd4-1 and Nedd4-2, and that aberrant PTEN ubiquitination is not involved in the impaired axon growth upon deletion of Nedd4-1 and Nedd4-2. Rather, PTEN limits Nedd4-1 protein levels by modulating the activity of mTORC1, a protein complex that controls protein synthesis and cell growth. Our data demonstrate that Nedd4-family E3 ligases promote axonal growth and branching in the developing mammalian brain, where PTEN is not a relevant substrate. Instead, PTEN controls neurite growth by regulating Nedd4-1 expression.