Akt and PP2A Reciprocally Regulate the Guanine Nucleotide Exchange Factor Dock6 to Control Axon Growth of Sensory Neurons
Akt and PP2A Reciprocally Regulate the Guanine Nucleotide Exchange Factor Dock6 to Control Axon Growth of Sensory Neurons
复制标题
DOI：
10.1126/scisignal.2003661
复制
发表时间：
2013-03-05
影响因子：
7.3
通讯作者：
Yamauchi, Junji
中科院分区：
文献类型：
--
作者：
Miyamoto, Yuki;Torii, Tomohiro;Yamauchi, Junji
在神经元发育过程中，轴突长距离导航，最终与周围组织等目标形成精确的连接。Dock 6是一种鸟嘌呤核苷酸交换因子（GEF），其激活Rho家族鸟苷三磷酸酶Rac 1和Cdc 42以调节肌动蛋白细胞骨架。我们发现Dock 6中Ser（1194）的磷酸化抑制了其GEF活性，并抑制了胚胎感觉神经元轴突生长和出生后感觉神经元轴突再生。在早期发育阶段，当轴突生长时，蛋白磷酸酶PP 2A与Dock 6相互作用并使其去磷酸化，从而增加Dock 6的活性。在发育后期，激酶Akt的丰度增加，导致Akt与Dock 6的结合和Dock 6在Ser（1194）处的磷酸化。在缺乏Dock 6的小鼠的背根神经节神经元中，重新引入具有不可磷酸化的S1194 A突变的Dock 6拯救了轴突延伸，但没有分支数量，而重新引入具有磷酸化模拟S1194 E突变的Dock 6导致过早分支。因此，Dock 6在Ser（1194）处的磷酸化状态决定了它是否促进感觉神经元中的轴突延伸或分支，揭示了轴突生长期间激酶和磷酸酶对Rho-GEF作用之间的相互作用。
During neuronal development, axons navigate long distances, eventually forming precise connections with such targets as peripheral tissues. Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. We found that phosphorylation of Ser(1194) in Dock6 inhibited its GEF activity and suppressed axonal growth of embryonic sensory neurons and axon regeneration of postnatal sensory neurons in vitro and in vivo. At early developmental stages, when axons are growing, the protein phosphatase PP2A interacted with and dephosphorylated Dock6, thereby increasing the activity of Dock6. At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching. Thus, the phosphorylation status of Dock6 at Ser(1194) determines whether it promotes axon extension or branching in sensory neurons, revealing interplay between kinase and phosphatase action on a Rho-GEF during axon growth.