3月11日出版的《发育细胞》(Developmental Cell)杂志报道了中国科学院上海生命科学研究院生物化学与细胞生物学研究所朱学良研究组的最新研究发现：Nudel蛋白在细胞迁移过程中通过Cdc42GAP调节Cdc42的活性，从而揭示了一条新的调节Cdc42的信号通路，对于深入了解细胞迁移的调节机制有重要意义。
细胞迁移是指细胞在固体支持物上的爬行运动。迁移是动物细胞的一种基本生命活动，在胚胎发育、神经系统形成、免疫等过程中都有重要作用，也与肿瘤转移密切相关。Cdc42是一种鸟嘌呤三核苷酸(GTP)酶，可以在活性形式和非活性形式间转换，从而作为分子“开关”在细胞迁移中行使多种重要的调节功能。Cdc42被鸟嘌呤核苷酸交换因子(GEF)激活，从而处于“开启”状态；活性的Cdc42可被GTP酶激活蛋白(GAP)失活，从而处于“关闭”状态。通常Cdc42只在位于细胞运动前缘的区域被激活。这种区域性的激活引起了微管和微丝等细胞骨架的极性分布，从而规定了细胞爬行的方向。在迁移过程中，细胞还会经常改变方向。因此，只有严格而且动态地控制处于活性状态的Cdc42的含量和分布，才能实现正常的迁移。过去的研究发现诱导细胞迁移的外界信号可以通过GEF区域性地激活Cdc42。然而，对于细胞在迁移过程中如何利用GAP调节Cdc42的活性，却所知甚少。
朱学良研究员的两位博士生沈义栋和李宁发现，血清等诱导细胞迁移的外界刺激可以通过激活蛋白激酶Erk使Nudel磷酸化。磷酸化的Nudel会富集到细胞的运动前缘。在那里Nudel通过与Cdc42竞争结合Cdc42的一个GAP蛋白-Cdc42GAP使由GEF激活的Cdc42能维持在活性状态。另一方面，过多的活性Cdc42也可以通过与Nudel竞争结合Cdc42GAP而失活。这一机理显然有助于细胞在迁移过程中对Cdc42的活性进行精细的动态调节。（来源：中科院上海生命科学研究院）
生物谷推荐原始出处：
(Developmental Cell)，Vol 14, 342-353, 11 March 2008，Yidong Shen, Xueliang Zhu
Nudel Binds Cdc42GAP to Modulate Cdc42 Activity at the Leading Edge of Migrating Cells
Yidong Shen, Ning Li, Shuang Wu, Yizhuo Zhou, Yongli Shan, Qiangge Zhang, Chong Ding, Quan Yuan, Fukun Zhao, Rong Zeng, and Xueliang Zhu
Summary
Cdc42GAP promotes inactivation of Cdc42, a small GTPase whose activation at the leading edge by guanine nucleotide exchange factors is critical for cell migration. How Cdc42GAP is regulated to ensure proper levels of active Cdc42 is poorly understood. Here we show that Nudel, a cytoplasmic dynein regulator, competes with Cdc42 for binding Cdc42GAP. Consequently, Nudel can inhibit Cdc42GAP-mediated inactivation of Cdc42 in a dose-dependent manner. Both Nudel and Cdc42GAP exhibit leading-edge localization in migrating cells. The localization of Nudel requires its phosphorylation by Erk1/2. Depleting Nudel by RNAi or overexpression of a nonphosphorylatable mutant abolishes Cdc42 activation and cell migration. Our data thus uncover Nudel as a regulator of Cdc42 during cell migration. Nudel facilitates cell migration by sequestering Cdc42GAP at the leading edge to stabilize active Cdc42 in response to extracellular stimuli. Excess active Cdc42 may in turn control its own activity by recruiting Cdc42GAP from Nudel.
