AJAM-A–tetraspanin–αvβ5 integrin complex regulates contact inhibition of locomotion
Kummer, Daniel; Steinbacher, Tim; Thölmann, Sonja; Schwietzer, Mariel Flavia; Hartmann, Christian; Horenkamp, Simone; Demuth, Sabrina; Peddibhotla, Swetha S.D.; Brinkmann, Frauke; Kemper, Björn; Schnekenburger, Jürgen; Brandt, Matthias; Betz, Timo; Liashkovich, Ivan; Kouzel, Ivan; Shahin, Victor; Corvaia, Nathalie; Rottner, Klemens; Tarbashevich, Katsiaryna; Raz, Erez; Greune, Lilo; Alexander Schmidt, Schmidt; Gerke, Volker; Ebnet, Klaus
Journal article, Peer reviewed
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Original versionJournal of Cell Biology. 2022, 221 (4), e202105147. 10.1083/jcb.202105147
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.