Shinoda Tomoyasu, Taya Shinichiro, Tsuboi Daisuke, Hikita Takao, Matsuzawa Reiko, Kuroda Setsuko, Iwamatsu Akihiro, Kaibuchi Kozo
Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Showa, Nagoya 466-8550, Japan.
J Neurosci. 2007 Jan 3;27(1):4-14. doi: 10.1523/JNEUROSCI.3825-06.2007.
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 14-3-3epsilon. 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.
精神分裂症相关基因1（DISC1）是精神分裂症易感性的候选基因。在随附论文（Taya等人，2006年）中，我们报告DISC1作为驱动蛋白-1与DISC1相互作用分子（如NudE样蛋白、无脑回蛋白-1和14-3-3ε）之间的连接物。在此，我们鉴定出生长因子受体结合蛋白2（Grb2）是一种新的DISC1相互作用分子。Grb2作为一种衔接分子，连接受体酪氨酸激酶和Ras-细胞外信号调节激酶（ERK）途径。DISC1与Grb2和驱动蛋白-1的驱动蛋白重链KIF5A形成三元复合物。在培养的大鼠海马神经元中，DISC1和Grb2都部分共定位于轴突远端。通过RNA干扰敲低DISC1或驱动蛋白-1的驱动蛋白轻链可抑制Grb2从轴突远端的积累。敲低DISC1还可抑制神经营养因子-3（NT-3）诱导的轴突远端ERK-1/2磷酸化，并抑制NT-3诱导的轴突伸长。这些结果表明，DISC1通过将Grb2募集到轴突末端，对NT-3诱导的轴突伸长和轴突远端ERK激活是必需的。
