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A JAM-A–tetraspanin–αvβ5 integrin complex regulates contact inhibition of locomotion
Journal of Cell Biology ( IF 7.4 ) Pub Date : 2022-03-16 , DOI: 10.1083/jcb.202105147
Daniel Kummer 1, 2, 3 , Tim Steinbacher 1, 2 , Sonja Thölmann 1, 2 , Mariel Flavia Schwietzer 1, 2 , Christian Hartmann 1, 2 , Simone Horenkamp 1, 2 , Sabrina Demuth 1, 2 , Swetha S D Peddibhotla 1, 2 , Frauke Brinkmann 1, 2 , Björn Kemper 4 , Jürgen Schnekenburger 4 , Matthias Brandt 5 , Timo Betz 5 , Ivan Liashkovich 6 , Ivan U Kouzel 7 , Victor Shahin 6 , Nathalie Corvaia 8 , Klemens Rottner 9, 10 , Katsiaryna Tarbashevich 11 , Erez Raz 11, 12 , Lilo Greune 13 , M Alexander Schmidt 13 , Volker Gerke 2, 12 , Klaus Ebnet 1, 2, 3, 12
Affiliation  

Contact inhibition of locomotion (CIL) is a process that regulates cell motility upon collision with other cells. Improper regulation of CIL has been implicated in cancer cell dissemination. Here, we identify the cell adhesion molecule JAM-A as a central regulator of CIL in tumor cells. JAM-A is part of a multimolecular signaling complex in which tetraspanins CD9 and CD81 link JAM-A to αvβ5 integrin. JAM-A binds Csk and inhibits the activity of αvβ5 integrin-associated Src. Loss of JAM-A results in increased activities of downstream effectors of Src, including Erk1/2, Abi1, and paxillin, as well as increased activity of Rac1 at cell–cell contact sites. As a consequence, JAM-A-depleted cells show increased motility, have a higher cell–matrix turnover, and fail to halt migration when colliding with other cells. We also find that proper regulation of CIL depends on αvβ5 integrin engagement. Our findings identify a molecular mechanism that regulates CIL in tumor cells and have implications on tumor cell dissemination.

中文翻译:

JAM-A-四跨膜蛋白-αvβ5 整合素复合物调节运动的接触抑制

运动接触抑制 (CIL) 是在与其他细胞碰撞时调节细胞运动的过程。CIL 的不当调节与癌细胞传播有关。在这里,我们将细胞粘附分子 JAM-A 确定为肿瘤细胞中 CIL 的中央调节因子。JAM-A 是多分子信号传导复合物的一部分,其中四跨膜蛋白 CD9 和 CD81 将 JAM-A 与 αvβ5 整联蛋白连接起来。JAM-A 结合 Csk 并抑制 αvβ5 整合素相关 Src 的活性。JAM-A 的缺失会导致 Src 下游效应器的活性增加,包括 Erk1/2、Abi1 和桩蛋白,以及细胞-细胞接触位点的 Rac1 活性增加。因此,JAM-A 耗尽的细胞显示出更强的运动性,具有更高的细胞基质周转率,并且在与其他细胞碰撞时无法停止迁移。我们还发现 CIL 的正确调节取决于 αvβ5 整合素的参与。我们的研究结果确定了调节肿瘤细胞中 CIL 的分子机制,并对肿瘤细胞传播产生影响。
更新日期:2022-03-16
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