Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
J Biol Chem. 2019 Oct 18;294(42):15435-15445. doi: 10.1074/jbc.RA119.009618. Epub 2019 Aug 30.
Akt signaling is an important regulator of neural development, but the distinctive function of Akt isoforms in brain development presents a challenge. Here we show Siah1 as an ubiquitin ligase that preferentially interacts with Akt3 and facilitates ubiquitination and degradation of Akt3. Akt3 is enriched in the axonal shaft and branches but not growth cone tips, where Siah1 is prominently present. Depletion of Siah1 enhanced Akt3 levels in the soma and axonal tips, eliciting multiple branching. Brain-specific somatic mutation in Akt3-E17K escapes from Siah1-mediated degradation and causes improper neural development with dysmorphic neurons. Remarkably, coexpression of Siah1 with Akt3-WT restricted disorganization of neural development is caused by Akt3 overexpression, whereas forced expression of Siah1 with the Akt3-E17K mutant fails to cope with malformation of neural development. These findings demonstrate that Siah1 limits Akt3 turnover during brain development and that this event is essential for normal organization of the neural network.
Akt 信号转导是神经发育的重要调节因子，但 Akt 同工型在大脑发育中的独特功能提出了挑战。在这里，我们发现 Siah1 是一种泛素连接酶，它优先与 Akt3 相互作用，促进 Akt3 的泛素化和降解。Akt3 在轴突干和分支中富集，但在生长锥尖端不富集，而 Siah1 在生长锥尖端大量存在。Siah1 的耗竭增加了 Akt3 在体部和轴突尖端的水平，引发了多次分支。大脑特异性 Akt3-E17K 的体细胞突变逃避了 Siah1 介导的降解，导致神经元形态异常的异常神经发育。值得注意的是，Siah1 与 Akt3-WT 的共表达限制了 Akt3 过表达引起的神经发育紊乱，而 Akt3-E17K 突变体的强制表达则无法应对神经发育的畸形。这些发现表明，Siah1 在大脑发育过程中限制了 Akt3 的周转率，而这一事件对于神经网络的正常组织是必不可少的。
