Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2
Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2
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DOI：
10.1038/sj.emboj.7600128
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发表时间：
2004-03-10
期刊：
影响因子：
11.4
通讯作者：
Sugimura, H
中科院分区：
文献类型：
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作者：
Tanaka, M;Ohashi, R;Sugimura, H
由Eph受体酪氨酸激酶及其膜结合配体ephrin介导的双向信号通过诱导神经突的塌陷和伸长在神经网络的形成中起关键作用。然而，传递这些信号的下游分子模块在很大程度上是未知的。我们在这里报告的Rac 1特异性鸟嘌呤核苷酸交换因子，Tiam 1，与ephrin-B1和EphA 2介导的神经突生长的相互作用。在共表达Tiam 1和肝配蛋白-B1的细胞中，Rac 1被成簇的可溶性EphB 2受体的细胞外刺激激活。类似地，可溶性肝配蛋白-A1激活共表达Tiam 1和EphA 2的细胞中的Rac 1。皮质神经元从E14小鼠胚胎和神经母细胞瘤细胞显着延长神经突起时，放置在表面上涂覆有胞外结构域的EphB 2或ephrin-A1，这是废除了强制表达的显性负突变体ephrin-B1或EphA 2。此外，Tiam 1的显性负性形式的引入也抑制了由肝配蛋白-B1和EphA 2信号诱导的神经突生长。这些结果表明，Tiam 1是必需的神经突起生长诱导ephrin-B1介导的反向信号和EphA 2介导的正向信号。
Bidirectional signals mediated by Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, play pivotal roles in the formation of neural networks by induction of both collapse and elongation of neurites. However, the downstream molecular modules to deliver these cues are largely unknown. We report here that the interaction of a Rac1-specific guanine nucleotide-exchanging factor, Tiam1, with ephrin-B1 and EphA2 mediates neurite outgrowth. In cells coexpressing Tiam1 and ephrin-B1, Rac1 is activated by the extracellular stimulation of clustered soluble EphB2 receptors. Similarly, soluble ephrin-A1 activates Rac1 in cells coexpressing Tiam1 and EphA2. Cortical neurons from the E14 mouse embryos and neuroblastoma cells significantly extend neurites when placed on surfaces coated with the extracellular domain of EphB2 or ephrin-A1, which were abolished by the forced expression of the dominant-negative mutant of ephrin-B1 or EphA2. Furthermore, the introduction of a dominant-negative form of Tiam1 also inhibits neurite outgrowth induced by the ephrin-B1 and EphA2 signals. These results indicate that Tiam1 is required for neurite outgrowth induced by both ephrin-B1-mediated reverse signaling and EphA2-mediated forward signaling.