mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system.
mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system.
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作者：
Miao L;Yang L;Huang H;Liang F;Ling C;Hu Y
在哺乳动物中，受伤的成熟中枢神经系统轴突不能再生。PI3K负调控因子PTEN的缺失通过激活PI3K- mtor信号通路诱导中枢神经系统轴突再生。我们对轴突再生中的交叉调节机制进行了广泛的分子解剖，其中涉及PI3K、AKT和两个mTOR复合物（mTORC1和mTORC2）的下游效应物。我们发现中枢神经系统中主要的AKT亚型AKT3诱导的轴突再生比AKT1强得多，mTORC1的激活和GSK3β的抑制是AKT诱导轴突再生的两个关键平行途径。令人惊讶的是，AKT的T308和S473磷酸化在GSK3β磷酸化和抑制中发挥相反的作用，mTORC2和pAKT-S473通过其负性调节轴突再生。因此，我们的研究揭示了一个复杂的神经元内在平衡机制，AKT作为PI3K、mTORC1/2和GSK3β的节点，协调正、负信号来调节成人中枢神经系统轴突再生。DOI: http://dx.doi.org/10.7554/eLife.14908.001中枢神经系统由构成大脑和脊髓的神经元组成。神经元的一个重要部分是电信号沿其传递的细长突起，称为轴突。在哺乳动物的中枢神经系统中，受损的轴突不能再生，这就是为什么脊髓损伤或视神经损伤会导致终生的神经元缺损。最近的研究发现，激活中枢神经系统神经元中的特定信号通路可导致其轴突再生。这一途径中的一个关键蛋白叫做AKT。AKT可触发多种信号级联反应来调节细胞的存活和生长，但目前尚不清楚AKT通路的不同分支如何参与轴突再生。Miao， Yang等人现在已经研究了AKT在轴突再生中的作用，使用一系列方法来操纵受损小鼠神经元的信号传导。这表明，一种特殊形式的AKT（称为AKT3）比其他形式的这种蛋白质更能引起受损轴突的再生。这种反应依赖于两条平行的途径：一条是AKT3激活一种叫做mTORC1的蛋白质复合物，另一条是AKT3抑制一种叫做GSK3β的蛋白质。此外，与mTORC1密切相关的另一种名为mTORC2的蛋白复合物有助于抑制AKT3对GSK3β的活性，从而抑制轴突再生。这些发现揭示了一个以AKT为中心的复杂平衡机制，协调了许多调节轴突再生的信号。未来对该系统的研究最终将有助于开发治疗脑和脊髓损伤的新方法。DOI: http://dx.doi.org/10.7554/eLife.14908.002
Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration. DOI: http://dx.doi.org/10.7554/eLife.14908.001 The central nervous system consists of the neurons that make up the brain and spinal cord. An important part of a neuron is the long, slender projection along which electrical signals travel, called the axon. In the central nervous system of mammals, damaged axons cannot regrow, which is why spinal injuries or optic nerve injuries can result in life-long neuronal deficits. Recent studies have found that activating a particular signaling pathway in central nervous system neurons causes their axons to regenerate. A key protein in this pathway is called AKT. Several signaling cascades are triggered by AKT to regulate cell survival and growth, but it was not known how the different branches of the AKT pathway are involved in axon regeneration. Miao, Yang et al. have now investigated AKT’s role in axon regeneration using a range of approaches to manipulate signaling in damaged mouse neurons. This revealed that a particular form of AKT (called AKT3) causes damaged axons to regenerate to a greater extent than other forms of this protein. This response depends on two parallel pathways: one in which AKT3 activates a protein complex called mTORC1, and one where AKT3 inhibits a protein called GSK3β. In addition, another protein complex called mTORC2, which is closely related to mTORC1, helps to inhibit the activity of AKT3 on GSK3β and hence inhibits axon regeneration. These findings reveal that a complex balancing mechanism, with AKT at its center, coordinates the many signals that regulate axon regeneration. Future studies into this system could ultimately help to develop new treatments for brain and spinal injuries. DOI: http://dx.doi.org/10.7554/eLife.14908.002