5月26日出版的《科学公共图书馆·生物学》(PLoS Biology)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：蛋白质Nudel和粘着斑激酶（FAK）通过与Paxillin发生竞争性结合，以相反的方式调节细胞的新生粘附位点（nascent adhesion）的强度。
细胞迁移在胚胎发生、免疫、创伤愈合等生理和炎症、癌细胞转移等病理过程中都有重要的作用。迁移可以看作是一个协调有序的细胞粘附和去粘附过程。细胞与胞外基质的粘附主要凭借整合素（Integrin）这个跨膜蛋白质家族介导的粘附来实现。整合素通过其胞内区域招募Paxillin和FAK等蛋白质分子组装成动态的细胞粘附结构并传递胞内外信号。体外培养的贴壁细胞在迁移时必须经历如下过程：（1）其运动前沿向前伸展并建立新生粘附位点；（2）随着运动前沿的继续前移，一些新生粘附位点因招募更多的整合素和胞内蛋白质分子而先后演变成与微丝骨架相连的粘着复合物（focal complex）和粘着斑（focal adhesion）。粘着斑总是成对出现，中间由粗壮的、具有收缩性的微丝束（张力丝）相连；（3）细胞的尾部收缩，使整个胞体向前移动，而这个过程需要尾部的粘着斑通过张力丝的牵拉而解聚。然而，微小的新生粘附位点为何比巨大的粘着斑更能抵抗细胞的收缩力却不清楚。
朱学良研究员的两位博士生单永立和余礼厚发现Nudel能与Paxillin直接结合，且二者被富集在细胞前缘伸展活跃的区域并发生共定位，但Nudel在成熟的粘附结构中则不存在。人为加强Nudel与Paxillin的相互作用能够增强粘附结构的强度，而抑制Nudel表达则降低新生粘附位点的生成率，导致细胞边缘的坍缩。进一步研究发现，Nudel与Paxillin之间的相互作用可被FAK通过竞争性结合Paxillin而阻断。FAK发挥这种作用需要打开其闭锁的自抑制分子结构，而不依赖于其激酶活性。而且，在细胞内过度表达FAK的Paxillin结合区也会导致细胞边缘的坍缩。这些结果揭示了细胞迁移中的一种新的分子机制：Nudel在细胞运动前沿结合Paxillin，从而选择性地增强整合素介导的新生粘附位点的强度以利于前缘的伸展；而在粘着斑中FAK与Paxillin的结合使单位粘附结构的粘附强度下降，从而有利于细胞尾部的收缩。
该研究项目得到了科技部、基金委、上海市科委和中科院的资助。（生物谷Bioon.com）
生物谷推荐原始出处：
PLoS Biol 7(5): e1000116. doi:10.1371/journal.pbio.1000116
Nudel and FAK as Antagonizing Strength Modulators of Nascent Adhesions through Paxillin
Yongli Shan#, Lihou Yu#, Yan Li, Youdong Pan, Qiangge Zhang, Fubin Wang, Jianfeng Chen, Xueliang Zhu*
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Adhesion and detachment are coordinated critical steps during cell migration. Conceptually, efficient migration requires both effective stabilization of membrane protrusions at the leading edge via nascent adhesions and their successful persistence during retraction of the trailing side via disruption of focal adhesions. As nascent adhesions are much smaller in size than focal adhesions, they are expected to exhibit a stronger adhesivity in order to achieve the coordination between cell front and back. Here, we show that Nudel knockdown by interference RNA (RNAi) resulted in cell edge shrinkage due to poor adhesions of membrane protrusions. Nudel bound to paxillin, a scaffold protein of focal contacts, and colocalized with it in areas of active membrane protrusions, presumably at nascent adhesions. The Nudel-paxillin interaction was disrupted by focal adhesion kinase (FAK) in a paxillin-binding–dependent manner. Forced localization of Nudel in all focal contacts by fusing it to paxillin markedly strengthened their adhesivity, whereas overexpression of structurally activated FAK or any paxillin-binding FAK mutant lacking the N-terminal autoinhibitory domain caused cell edge shrinkage. These results suggest a novel mechanism for selective reinforcement of nascent adhesions via interplays of Nudel and FAK with paxillin to facilitate cell migration.
