3月11日出版的《發(fā)育細胞》(Developmental Cell)雜志報道了中國科學院上海生命科學研究院生物化學與細胞生物學研究所朱學良研究組的最新研究發(fā)現(xiàn)：Nudel蛋白在細胞遷移過程中通過Cdc42GAP調(diào)節(jié)Cdc42的活性,，從而揭示了一條新的調(diào)節(jié)Cdc42的信號通路，對于深入了解細胞遷移的調(diào)節(jié)機制有重要意義,。
細胞遷移是指細胞在固體支持物上的爬行運動,。遷移是動物細胞的一種基本生命活動,，在胚胎發(fā)育、神經(jīng)系統(tǒng)形成,、免疫等過程中都有重要作用,，也與腫瘤轉(zhuǎn)移密切相關(guān)。Cdc42是一種鳥嘌呤三核苷酸(GTP)酶,，可以在活性形式和非活性形式間轉(zhuǎn)換,，從而作為分子“開關(guān)”在細胞遷移中行使多種重要的調(diào)節(jié)功能。Cdc42被鳥嘌呤核苷酸交換因子(GEF)激活,，從而處于“開啟”狀態(tài),；活性的Cdc42可被GTP酶激活蛋白(GAP)失活，從而處于“關(guān)閉”狀態(tài),。通常Cdc42只在位于細胞運動前緣的區(qū)域被激活,。這種區(qū)域性的激活引起了微管和微絲等細胞骨架的極性分布，從而規(guī)定了細胞爬行的方向,。在遷移過程中,，細胞還會經(jīng)常改變方向。因此,，只有嚴格而且動態(tài)地控制處于活性狀態(tài)的Cdc42的含量和分布，才能實現(xiàn)正常的遷移,。過去的研究發(fā)現(xiàn)誘導細胞遷移的外界信號可以通過GEF區(qū)域性地激活Cdc42,。然而,，對于細胞在遷移過程中如何利用GAP調(diào)節(jié)Cdc42的活性，卻所知甚少,。
朱學良研究員的兩位博士生沈義棟和李寧發(fā)現(xiàn),，血清等誘導細胞遷移的外界刺激可以通過激活蛋白激酶Erk使Nudel磷酸化。磷酸化的Nudel會富集到細胞的運動前緣,。在那里Nudel通過與Cdc42競爭結(jié)合Cdc42的一個GAP蛋白-Cdc42GAP使由GEF激活的Cdc42能維持在活性狀態(tài),。另一方面，過多的活性Cdc42也可以通過與Nudel競爭結(jié)合Cdc42GAP而失活,。這一機理顯然有助于細胞在遷移過程中對Cdc42的活性進行精細的動態(tài)調(diào)節(jié),。（來源：中科院上海生命科學研究院）
生物谷推薦原始出處：
(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.
