DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2
DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2
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DOI：
10.1523/jneurosci.3825-06.2007
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发表时间：
2007-01-03
影响因子：
5.3
通讯作者：
Kaibuchi, Kozo
中科院分区：
文献类型：
--
作者：
Shinoda, Tomoyasu;Taya, Shinichiro;Kaibuchi, Kozo
DISC1基因是精神分裂症易感性的候选基因。在随附的论文中(Taya等人，2006年)，我们报告了DISC1作为Kinesin-1和DISC1相互作用分子之间的连接物，例如裸体样分子、无脑-1分子和14-3-3 epsilon。在此，我们发现生长因子受体结合蛋白2(Grb2)是一种与DISC1相互作用的新分子。Grb2是一种连接受体酪氨酸激酶和RAS-细胞外信号调节激酶(ERK)通路的接头分子。DISC1与Grb2和Kinesin重链KIF5A形成了一个三元复合体。在培养的大鼠海马神经元中，DISC1和Grb2部分共存于轴突远端。RNA干扰敲除DISC1或kinesin轻链的kinesin-1可抑制Grb2在轴突远端的积聚。DISC1基因敲除还可抑制神经营养素-3(NT-3)诱导的ERK-1/2在轴突远端的磷酸化，并抑制NT-3诱导的轴突延长。这些结果表明，DISC1是NT-3通过将Grb2招募到轴突尖端而在轴突远端诱导轴突延长和ERK激活所必需的。
Disrupted-in-Schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3 epsilon. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras-extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.