Laboratory of Molecular and Cellular Neuroscience, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
PLoS One. 2010 Mar 19;5(3):e9647. doi: 10.1371/journal.pone.0009647.
Nerve Growth Factor (NGF)-induced neuronal differentiation requires the activation of members of the Rho family of small GTPases. However, the molecular mechanisms through which NGF regulates cytoskeletal changes and neurite outgrowth are not totally understood. In this work, we identify the Rac1-specific guanine exchange factor (GEF) Tiam1 as a novel mediator of NGF/TrkA-dependent neurite elongation. In particular, we report that knockdown of Tiam1 causes a significant reduction in Rac1 activity and neurite outgrowth induced by NGF. Physical interaction between Tiam1 and active Ras (Ras-GTP), but not tyrosine phosphorylation of Tiam1, plays a central role in Rac1 activation by NGF. In addition, our findings indicate that Ras is required to associate Tiam1 with Rac1 and promote Rac1 activation upon NGF stimulation. Taken together, these findings define a novel molecular mechanism through which Tiam1 mediates TrkA signaling and neurite outgrowth induced by NGF.
神经生长因子（NGF）诱导的神经元分化需要 Rho 家族小 GTPases 成员的激活。然而，NGF 调节细胞骨架变化和神经突生长的分子机制尚未完全阐明。在这项工作中，我们确定 Rac1 特异性鸟嘌呤交换因子（GEF）Tiam1 是 NGF/TrkA 依赖性神经突伸长的新介质。具体而言，我们报告说，Tiam1 的敲低导致 NGF 诱导的 Rac1 活性和神经突生长显著减少。Tiam1 与活性 Ras（Ras-GTP）之间的物理相互作用，而不是 Tiam1 的酪氨酸磷酸化，在 NGF 激活 Rac1 中起核心作用。此外，我们的发现表明 Ras 是将 Tiam1 与 Rac1 相关联并在 NGF 刺激时促进 Rac1 激活所必需的。总之，这些发现定义了 Tiam1 介导 NGF 诱导的 TrkA 信号转导和神经突生长的新分子机制。
