Brouns M R, Matheson S F, Settleman J
MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Nat Cell Biol. 2001 Apr;3(4):361-7. doi: 10.1038/35070042.
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 co-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.
Src酪氨酸激酶与神经发育和神经系统功能的多个方面有关；然而，它们在大脑中的相关底物及其在神经元中的作用机制仍有待明确。在此，我们确定了强效的Rho调节蛋白p190 RhoGAP（GTP酶激活蛋白）是在发育中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束状化方面存在缺陷。p190 RhoGAP与F-肌动蛋白在轴突远端尖端共同富集，并且在神经母细胞瘤细胞中过表达p190 RhoGAP可促进广泛的神经突生长，这表明p190 RhoGAP可能是Rho介导的神经元生长锥中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，并且我们发现细胞外基质蛋白层粘连蛋白可促进p190-RhoGAP介导的神经突生长。连同缺乏神经粘附分子或Src激酶的小鼠在轴突生长、导向和束状化方面也存在缺陷这一事实，我们的结果表明p190 RhoGAP通过Rho GTP酶介导了一种Src依赖性的粘附信号，用于神经突发生至肌动蛋白细胞骨架。
