Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility
Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility
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DOI：
10.1038/nn1619
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发表时间：
2006-01-01
影响因子：
25
通讯作者：
Ross, ME
中科院分区：
文献类型：
--
作者：
Kholmanskikh, SS;Koeller, HB;Ross, ME
Lis 1基因缺陷损害神经元迁移，导致严重的人类脑畸形无脑畸形。尽管人们对Lis 1与微管、微管结合蛋白（如CLIP-170）以及动力蛋白运动复合体的相互作用了解很多，但Lis 1对神经元运动信号的反应尚未阐明。Lis 1缺陷与Rho家族GTP酶Cdc 42、Rac 1和RhoA的失调以及随后的肌动蛋白细胞骨架缺陷有关，但Lis 1和Rho GTP酶之间的联系尚不清楚。我们在这里报告，钙离子内流增强神经元的运动，通过Lis 1依赖性调节Rho GTPases。Lis 1通过与钙敏感性GT3支架蛋白IQGAP 1相互作用促进Cdc 42活化，维持IQGAP 1和CLIP 170的膜周定位，从而将微管末端拴系到皮质肌动蛋白细胞骨架。因此，Lis 1是神经元运动信号转导的关键组分，其在钙内流时通过与IQGAP 1、活性Cdc 42和CLIP-170复合来调节细胞骨架。
Lis1 gene defects impair neuronal migration, causing the severe human brain malformation lissencephaly. Although much is known about its interactions with microtubules, microtubule-binding proteins such as CLIP-170, and with the dynein motor complex, the response of Lis1 to neuronal motility signals has not been elucidated. Lis1 deficiency is associated with deregulation of the Rho-family GTPases Cdc42, Rac1 and RhoA, and ensuing actin cytoskeletal defects, but the link between Lis1 and Rho GTPases remains unclear. We report here that calcium influx enhances neuronal motility through Lis1-dependent regulation of Rho GTPases. Lis1 promotes Cdc42 activation through interaction with the calcium sensitive GTPase scaffolding protein IQGAP1, maintaining the perimembrane localization of IQGAP1 and CLIP170 and thereby tethering microtubule ends to the cortical actin cytoskeleton. Lis1 thus is a key component of neuronal motility signal transduction that regulates the cytoskeleton by complexing with IQGAP1, active Cdc42 and CLIP-170 upon calcium influx.