A JAM-A – tetraspanin – αvβ5 integrin complex regulates contact inhibition of locomotion.

Kummer D; Steinbacher T; Thölmann S; Schwietzer MF; Hartmann C; Horenkamp S; Demuth S; Peddibhotla SSD; Brinkmann F; Kemper B; Schnekenburger J; Brandt M; Betz T; Liashkovich I; Koutel IU; Shahin V; Corvaia N; Rottner K; Tarbashevich K; Raz E; Greune L; Schmidt MA; Gerke V; Ebnet K

Abstract

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.