Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Genes Cells. 2012 Aug;17(8):688-97. doi: 10.1111/j.1365-2443.2012.01616.x. Epub 2012 Jun 27.
Dock3, a new member of the guanine nucleotide exchange factor family, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes neurite outgrowth through the formation of a protein complex with Fyn and WAVE downstream of brain-derived neurotrophic factor (BDNF) signaling. Here, we report a novel Dock3-mediated BDNF pathway for neurite outgrowth. We show that Dock3 forms a complex with Elmo and activated RhoG downstream of BDNF-TrkB signaling and induces neurite outgrowth via Rac1 activation in PC12 cells. We also show the importance of Dock3 phosphorylation in Rac1 activation and show two key events that are necessary for efficient Dock3 phosphorylation: membrane recruitment of Dock3 and interaction of Dock3 with Elmo. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the central nervous system where it stimulates actin polymerization by multiple pathways.
Dock3 是鸟嘌呤核苷酸交换因子家族的新成员，通过激活小 GTP 酶 Rac1 引起细胞形态变化。在神经细胞中过表达 Dock3 通过与 Fyn 和 WAVE 形成蛋白质复合物促进神经突生长，该复合物是在脑源性神经营养因子 (BDNF) 信号的下游形成的。在这里，我们报告了一种新的 Dock3 介导的 BDNF 通路促进神经突生长。我们表明，Dock3 在 BDNF-TrkB 信号的下游与 Elmo 和激活的 RhoG 形成复合物，并通过 Rac1 的激活在 PC12 细胞中诱导神经突生长。我们还表明了 Dock3 磷酸化在 Rac1 激活中的重要性，并显示了有效 Dock3 磷酸化所必需的两个关键事件：Dock3 的膜募集和 Dock3 与 Elmo 的相互作用。这些结果表明，Dock3 在中枢神经系统中 BDNF 信号的下游发挥重要作用，通过多种途径刺激肌动蛋白聚合。
