Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility

被引:136
|
作者
Kholmanskikh, SS
Koeller, HB
Wynshaw-Boris, A
Gomez, T
Letourneau, PC
Ross, ME
机构
[1] Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA
[2] Univ Calif San Diego, San Diego Sch Med, Dept Pediat, La Jolla, CA 92093 USA
[3] Univ Wisconsin, Sch Med, Dept Neurosci, Madison, WI 53706 USA
[4] Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA
关键词
D O I
10.1038/nn1619
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:50 / 57
页数:8
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