Unc-51-like kinase 1/2-mediated endocytic processes regulate filopodia extension and branching of sensory axons
Unc-51-like kinase 1/2-mediated endocytic processes regulate filopodia extension and branching of sensory axons
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DOI：
10.1073/pnas.0701402104
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发表时间：
2007-04
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影响因子：
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通讯作者：
Xiaoping Zhou;J. Babu;Susana da Silva;Qing Shu;I. Graef;T. Oliver;T. Tomoda;T. Tani;M. W. Wooten;Fan Wang
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文献类型：
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作者：
Xiaoping Zhou;J. Babu;Susana da Silva;Qing Shu;I. Graef;T. Oliver;T. Tomoda;T. Tani;M. W. Wooten;Fan Wang
涉及定向轴突延长的内吞过程的分子机制和意义尚不清楚。UNC-51丝氨酸/苏氨酸激酶家族被证明对轴突生长很重要，也与内吞作用有关，这为研究这一问题提供了一个切入点。我们发现小鼠UNC-51-like kinase1/2(Ulk1/2)蛋白定位于小鼠脊髓感觉神经元生长锥内的囊泡结构。RNAi介导的Ulk1和/或Ulk2基因敲除导致神经生长因子(NGF)的内吞功能受损，轴突过度分枝，轴突伸长严重受阻。证据还表明，Ulk1/2在感觉生长锥体中介导了一种非笼状蛋白包裹的内吞作用。有趣的是，NGF可以通过促进Ulk1的K63泛素化和与支架蛋白p62的结合来诱导Ulk1与TrkA受体复合体的相互作用。这些结果和其他研究表明，Ulk1/2蛋白可能通过调节TrkA受体的运输和信号，调节感觉神经轴突生长过程中丝足的延伸和轴突的分支。
The molecular mechanism and significance of endocytic processes involved in directional axon elongation are not well understood. The Unc-51 family of serine/threonine kinases was shown to be important for axon growth and was also linked to endocytosis, providing an entry point to study this problem. We found that mouse Unc-51-like kinase 1/2 (Ulk1/2) proteins are localized to vesicular structures in growth cones of mouse spinal sensory neurons. RNAi-mediated knockdown of Ulk1 and/or Ulk2 resulted in impaired endocytosis of nerve growth factor (NGF), excessive axon arborization, and severely stunted axon elongation. The evidence also indicates that Ulk1/2 mediates a non-clathrin-coated endocytosis in sensory growth cones. Interestingly, NGF can induce the interaction of Ulk1 with TrkA receptor complexes through promoting K63-polyubiquitination of Ulk1 and binding of Ulk1 to the scaffolding protein p62. These results and additional studies suggest that Ulk1/2 proteins regulate filopodia extension and neurite branching during sensory axon outgrowth, probably through regulating TrkA receptor trafficking and signaling.