5月26日出版的《科學(xué)公共圖書館·生物學(xué)》(PLoS Biology)雜志報道了中國科學(xué)院上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所朱學(xué)良研究組的最新研究發(fā)現(xiàn)：蛋白質(zhì)Nudel和粘著斑激酶（FAK）通過與Paxillin發(fā)生競爭性結(jié)合，以相反的方式調(diào)節(jié)細(xì)胞的新生粘附位點(diǎn)（nascent adhesion）的強(qiáng)度,。
細(xì)胞遷移在胚胎發(fā)生,、免疫、創(chuàng)傷愈合等生理和炎癥,、癌細(xì)胞轉(zhuǎn)移等病理過程中都有重要的作用,。遷移可以看作是一個協(xié)調(diào)有序的細(xì)胞粘附和去粘附過程,。細(xì)胞與胞外基質(zhì)的粘附主要憑借整合素（Integrin）這個跨膜蛋白質(zhì)家族介導(dǎo)的粘附來實(shí)現(xiàn)。整合素通過其胞內(nèi)區(qū)域招募Paxillin和FAK等蛋白質(zhì)分子組裝成動態(tài)的細(xì)胞粘附結(jié)構(gòu)并傳遞胞內(nèi)外信號,。體外培養(yǎng)的貼壁細(xì)胞在遷移時必須經(jīng)歷如下過程：（1）其運(yùn)動前沿向前伸展并建立新生粘附位點(diǎn)；（2）隨著運(yùn)動前沿的繼續(xù)前移,，一些新生粘附位點(diǎn)因招募更多的整合素和胞內(nèi)蛋白質(zhì)分子而先后演變成與微絲骨架相連的粘著復(fù)合物（focal complex）和粘著斑（focal adhesion）,。粘著斑總是成對出現(xiàn),，中間由粗壯的,、具有收縮性的微絲束（張力絲）相連；（3）細(xì)胞的尾部收縮,，使整個胞體向前移動,，而這個過程需要尾部的粘著斑通過張力絲的牽拉而解聚。然而,，微小的新生粘附位點(diǎn)為何比巨大的粘著斑更能抵抗細(xì)胞的收縮力卻不清楚,。
朱學(xué)良研究員的兩位博士生單永立和余禮厚發(fā)現(xiàn)Nudel能與Paxillin直接結(jié)合，且二者被富集在細(xì)胞前緣伸展活躍的區(qū)域并發(fā)生共定位,，但Nudel在成熟的粘附結(jié)構(gòu)中則不存在,。人為加強(qiáng)Nudel與Paxillin的相互作用能夠增強(qiáng)粘附結(jié)構(gòu)的強(qiáng)度，而抑制Nudel表達(dá)則降低新生粘附位點(diǎn)的生成率,，導(dǎo)致細(xì)胞邊緣的坍縮,。進(jìn)一步研究發(fā)現(xiàn)，Nudel與Paxillin之間的相互作用可被FAK通過競爭性結(jié)合Paxillin而阻斷,。FAK發(fā)揮這種作用需要打開其閉鎖的自抑制分子結(jié)構(gòu),，而不依賴于其激酶活性。而且,，在細(xì)胞內(nèi)過度表達(dá)FAK的Paxillin結(jié)合區(qū)也會導(dǎo)致細(xì)胞邊緣的坍縮,。這些結(jié)果揭示了細(xì)胞遷移中的一種新的分子機(jī)制：Nudel在細(xì)胞運(yùn)動前沿結(jié)合Paxillin,，從而選擇性地增強(qiáng)整合素介導(dǎo)的新生粘附位點(diǎn)的強(qiáng)度以利于前緣的伸展；而在粘著斑中FAK與Paxillin的結(jié)合使單位粘附結(jié)構(gòu)的粘附強(qiáng)度下降,，從而有利于細(xì)胞尾部的收縮,。
該研究項目得到了科技部、基金委,、上海市科委和中科院的資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
