The activation of ezrin-radixin-moesin proteins is regulated by netrin-1 through Src kinase and RhoA/Rho kinase activities and mediates netrin-1-induced axon outgrowth.
The activation of ezrin-radixin-moesin proteins is regulated by netrin-1 through Src kinase and RhoA/Rho kinase activities and mediates netrin-1-induced axon outgrowth.
复制标题
DOI：
10.1091/mbc.e10-11-0917
复制
发表时间：
2011-10
影响因子：
3.3
通讯作者：
Lamarche-Vane N
中科院分区：
文献类型：
--
作者：
Antoine-Bertrand J;Ghogha A;Luangrath V;Bedford FK;Lamarche-Vane N
轴突导向因子netrin-1及其受体DCC调节轴突生长。Netrin-1诱导ERM蛋白的活化及其与皮质神经元中DCC的关联，并且ERM蛋白的活性是Netrin-1依赖性轴突生长所需的。结直肠癌（DCC）中的受体介导轴突在发育过程中对导向因子netrin-1的吸引反应。在netrin-1刺激下，DCC被磷酸化，并诱导生长锥内信号复合物的组装，导致细胞骨架调节剂，即GTP酶Rac 1和Cdc 42的激活。netrin-1/DCC与肌动蛋白机制的分子机制尚不清楚。在这项研究中，我们试图证明肌动蛋白结合蛋白ezrin-radixin-moesin（ERM）是胚胎皮质神经元中netrin-1/DCC信号传导的效应子。我们发现，ezrin协会与DCC在netrin-1依赖的方式。我们证明netrin-1/DCC诱导ERM磷酸化和激活，DCC的磷酸化是必需的。此外，Src激酶和RhoA/Rho激酶活性介导netrin-1诱导的神经元中的ERM磷酸化。我们还观察到磷酸化的ERM蛋白在生长锥丝状伪足中积累，在那里它们在netrin-1刺激后与DCC共定位。最后，我们发现，在皮层神经元中ezrin表达的损失显着减少轴突生长诱导netrin-1。总之，我们的研究结果表明，netrin-1诱导形成一个激活的ERM/DCC复合物的生长锥丝状伪足，这是需要netrin-1依赖的皮质轴突生长。
The axon guidance cue netrin-1 and its receptor DCC regulate axon outgrowth. Netrin-1 induces the activation of ERM proteins and their association with DCC in cortical neurons, and the activity of ERM proteins is required for netrin-1–dependent axon outgrowth. The receptor Deleted in Colorectal Cancer (DCC) mediates the attractive response of axons to the guidance cue netrin-1 during development. On netrin-1 stimulation, DCC is phosphorylated and induces the assembly of signaling complexes within the growth cone, leading to activation of cytoskeleton regulators, namely the GTPases Rac1 and Cdc42. The molecular mechanisms that link netrin-1/DCC to the actin machinery remain unclear. In this study we seek to demonstrate that the actin-binding proteins ezrin–radixin–moesin (ERM) are effectors of netrin-1/DCC signaling in embryonic cortical neurons. We show that ezrin associates with DCC in a netrin-1–dependent manner. We demonstrate that netrin-1/DCC induces ERM phosphorylation and activation and that the phosphorylation of DCC is required in that context. Moreover, Src kinases and RhoA/Rho kinase activities mediate netrin-1–induced ERM phosphorylation in neurons. We also observed that phosphorylated ERM proteins accumulate in growth cone filopodia, where they colocalize with DCC upon netrin-1 stimulation. Finally, we show that loss of ezrin expression in cortical neurons significantly decreases axon outgrowth induced by netrin-1. Together, our findings demonstrate that netrin-1 induces the formation of an activated ERM/DCC complex in growth cone filopodia, which is required for netrin-1–dependent cortical axon outgrowth.