p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation
p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation
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DOI：
10.1038/35070042
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发表时间：
2001-04-01
影响因子：
21.3
通讯作者：
Settleman, J
中科院分区：
文献类型：
--
作者：
Brouns, MR;Matheson, SF;Settleman, J
Src酪氨酸激酶参与神经发育和神经系统功能的多个方面;然而，它们在脑中的相关底物及其在神经元中的作用机制仍有待明确。在这里，我们确定了有效的Rho调节蛋白，p190 RhoGAP（GTP酶激活蛋白），作为在发育和成熟的神经系统中检测到的主要Src底物。我们还发现，缺乏功能性p190 RhoGAP的小鼠在轴突导向和成束方面表现出缺陷，p190 RhoGAP在轴突的远端尖端富含F-actin，并且在神经母细胞瘤细胞中过表达p190 RhoGAP促进了广泛的神经突生长，这表明p190 RhoGAP可能是神经生长锥中Rho介导的肌动蛋白重组的重要调节因子。p190 RhoGAP转导细胞表面粘附分子下游的信号，我们发现p190-RhoGAP介导的神经突生长是由细胞外基质蛋白层粘连蛋白促进的。再加上缺乏神经粘附分子或Src激酶的小鼠也表现出轴突生长，指导和成束的缺陷，我们的研究结果表明，p190 RhoGAP介导的Src依赖性的粘附信号，通过Rho GTdR的肌动蛋白细胞骨架的轴突发生。
The Src tyrosine kinases have been implicated in several aspects of neural development and nervous system function; however, their relevant substrates in brain and their mechanism of action in neurons remain to be established clearly. Here we identify the potent Rho regulatory protein, p190 RhoGAP (GTPase-activating protein), as the principal Src substrate detected in the developing and mature nervous system. We also find that mice lacking functional p190 RhoGAP exhibit defects in axon guidance and fasciculation, p190 RhoGAP is cc-enriched with F-actin in the distal tips of axons, and overexpressing p190 RhoGAP in neuroblastoma cells promotes extensive neurite outgrowth, indicating that p190 RhoGAP may be an important regulator of Rho-mediated actin reorganization in neuronal growth cones. p190 RhoGAP transduces signals downstream of cell-surface adhesion molecules, and we find that p190-RhoGAP-mediated neurite outgrowth is promoted by the extracellular matrix protein laminin. Together with the fact that mice lacking neural adhesion molecules or Src kinases also exhibit defects in axon outgrowth, guidance and fasciculation, our results suggest that p190 RhoGAP mediates a Src-dependent adhesion signal for neuritogenesis to the actin cytoskeleton through the Rho GTPase.