Nerve growth factor-mediated neurite outgrowth via regulation of Rab5
Nerve growth factor-mediated neurite outgrowth via regulation of Rab5
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DOI：
10.1091/mbc.e06-08-0725
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发表时间：
2007-04-01
影响因子：
3.3
通讯作者：
Li, Guangpu
中科院分区：
文献类型：
--
作者：
Liu, Jay;Lamb, Darija;Li, Guangpu
神经生长因子（NGF）诱导神经突生长和分化的过程包括NGF与其受体TrkA结合，并将NGF-TrkA复合物内吞成信号内体。在这里，我们发现信号核内体的生物发生需要Rab5失活来阻止早期核内体融合。Rab5显性阴性突变体的表达增强了ngf介导的神经突生长，而组成型活性Rab5突变体或Rabex-5则抑制了这一过程。一致地，Rab5的失活维持了内体上TrkA的激活。此外，NGF处理可迅速降低Rab5-GTP的细胞活性水平。RabGAP5介导了RabGAP5的下调，通过共免疫沉淀实验显示RabGAP5与TrkA相关。重要的是，RabGAP5的RNA干扰以及含有trka结合域的RabGAP5截断突变体阻断了ngf介导的神经突生长，表明RabGAP5在这一过程中是必需的。因此，NGF信号通过RabGAP5下调Rab5活性，促进神经突的生长和分化。
Nerve growth factor (NGF) induces neurite outgrowth and differentiation in a process that involves NGF binding to its receptor TrkA and endocytosis of the NGF-TrkA complex into signaling endosomes. Here, we find that biogenesis of signaling endosomes requires inactivation of Rab5 to block early endosome fusion. Expression of dominant-negative Rab5 mutants enhanced NGF-mediated neurite outgrowth, whereas a constitutively active Rab5 mutant or Rabex-5 inhibited this process. Consistently, inactivation of Rab5 sustained TrkA activation on the endosomes. Furthermore, NGF treatment rapidly decreased cellular level of active Rab5-GTP, as shown by pull-down assays. This Rab5 down-regulation was mediated by RabGAP5, which was shown to associate with TrkA by coimmunoprecipitation assays. Importantly, RNA interference of RabGAP5 as well as a RabGAP5 truncation mutant containing the TrkA-binding domain blocked NGF-mediated neurite outgrowth, indicating a requirement for RabGAP5 in this process. Thus, NGF signaling down-regulates Rab5 activity via RabGAP5 to facilitate neurite outgrowth and differentiation.