EPHA-mediated growth cone collapse

EPH/Ephrin signaling is coupled to Rho family GTPases such as Rac, Rho and Cdc42 that connect bidirectional receptor-ligand interactions to changes in the actin cytoskeleton (Noren & Pasquale 2004, Groeger & Nobes 2007). RHOA regulates actin dynamics and is involved in EPHA-induced growth cone collapse. This is mediated by ephexins. Ephexin, a guanine nucleotide exchange factor for Rho GTPases, interacts with the EPHA kinase domain and its subsequent activation differentially affects Rho GTPases, such that RHOA is activated, whereas Cdc42 and Rac1 are inhibited. Activation of RHOA, and inhibition of Cdc42 and Rac, shifts actin cytoskeleton to increased contraction and reduced expansion leading to growth-cone collapse (Shamah et al. 2001, Sahin et al. 2005). The activation of EPH receptors in growing neurons typically, but not always, leads to a growth cone collapse response and retraction from an ephrin-expressing substrate (Poliakov et al. 2004, Pasquale 2005). EPHA-mediated repulsive responses prevent axons from growing into regions of excessive ephrin-A concentration, such as the posterior end of the superior colliculus (Pasquale 2005).

EPH/ Ephrin 信号传导与Rho家族GTP酶（如Rac、Rho和Cdc42）紧密相连，这些GTP酶将双向受体-配体相互作用与细胞骨架肌动蛋白的变化相联系（Noren & Pasquale, 2004; Groeger & Nobes, 2007）。RHOA调节肌动蛋白的动态变化，并参与EPHA诱导的生长锥塌陷。这一过程由ephexins介导。Ephexin是Rho GTP酶的鸟苷酸交换因子，它与EPHA激酶域相互作用，并随后激活，从而不同地影响Rho GTP酶，导致RHOA被激活，而Cdc42和Rac1被抑制。RHOA的激活以及Cdc42和Rac的抑制，使肌动蛋白细胞骨架向增强收缩和减少扩张转变，从而导致生长锥塌陷（Shamah等，2001; Sahin等，2005）。在生长中的神经元中，EPH受体的激活通常（但并非总是）会导致生长锥塌陷反应和从表达Ephrin的底物上的退缩（Poliakov等，2004; Pasquale, 2005）。EPHA介导的排斥反应防止轴突生长进入Ephrin-A浓度过高的区域，例如上丘的尾端（Pasquale, 2005）。