Sahin Mustafa, Greer Paul L, Lin Michael Z, Poucher Heather, Eberhart Johann, Schmidt Susanne, Wright Tracy M, Shamah Steven M, O'connell Sinead, Cowan Christopher W, Hu Linda, Goldberg Jeffrey L, Debant Anne, Corfas Gabriel, Krull Catherine E, Greenberg Michael E
Neurobiology Program, Children's Hospital, Boston, Massachusetts 02115, USA.
Neuron. 2005 Apr 21;46(2):191-204. doi: 10.1016/j.neuron.2005.01.030.
Ephs regulate growth cone repulsion, a process controlled by the actin cytoskeleton. The guanine nucleotide exchange factor (GEF) ephexin1 interacts with EphA4 and has been suggested to mediate the effect of EphA on the activity of Rho GTPases, key regulators of the cytoskeleton and axon guidance. Using cultured ephexin1-/- mouse neurons and RNA interference in the chick, we report that ephexin1 is required for normal axon outgrowth and ephrin-dependent axon repulsion. Ephexin1 becomes tyrosine phosphorylated in response to EphA signaling in neurons, and this phosphorylation event is required for growth cone collapse. Tyrosine phosphorylation of ephexin1 enhances ephexin1's GEF activity toward RhoA while not altering its activity toward Rac1 or Cdc42, thus changing the balance of GTPase activities. These findings reveal that ephexin1 plays a role in axon guidance and is regulated by a switch mechanism that is specifically tailored to control Eph-mediated growth cone collapse.
Eph 蛋白调节生长锥排斥作用，这一过程由肌动蛋白细胞骨架控制。鸟嘌呤核苷酸交换因子（GEF）ephexin1 与 EphA4 相互作用，有人认为它介导 EphA 对 Rho GTP 酶活性的影响，Rho GTP 酶是细胞骨架和轴突导向的关键调节因子。利用培养的 ephexin1 基因敲除小鼠神经元以及在鸡中进行 RNA 干扰，我们发现 ephexin1 是正常轴突生长和 ephrin 依赖性轴突排斥所必需的。在神经元中，ephexin1 会响应 EphA 信号而发生酪氨酸磷酸化，并且这种磷酸化事件是生长锥塌陷所必需的。ephexin1 的酪氨酸磷酸化增强了其对 RhoA 的 GEF 活性，同时不改变其对 Rac1 或 Cdc42 的活性，从而改变了 GTP 酶活性的平衡。这些发现揭示，ephexin1 在轴突导向中发挥作用，并受一种专门用于控制 Eph 介导的生长锥塌陷的开关机制调节。
