Connexin46 Modulates Cancer Cell Migration Through a Channel- Independent Mechanism

Cell migration is a central process in cancer progression and metastatic dissemination. While connexins (Cxs) classically mediate cell–cell communication through the formation of gap junction channels and hemichannels, accumulating evidence supports additional channel-independent roles in tumor cell signaling. Cx46 is a member of the Cx family with a highly restricted expression pattern under physiological conditions, thus, in humans it has been reported primarily in the eye lens. Interestingly, Cx46 is aberrantly expressed in several types of cancer cells, where it has been implicated in the acquisition of mesenchymal traits and cancer stem cell–like properties. In this study, we identify a previously unrecognized signaling function of Cx46 in the regulation of cancer cell migration. We show that Cx46 expression suppresses migration in HeLa cells. This anti-migratory effect is mediated by the C-terminal domain of Cx46, as deletion of this region abolishes the inhibitory phenotype. Furthermore, we demonstrate that Cx46 directly interacts with Src kinase, promoting Src localization at the plasma membrane and inducing concomitant changes in the intracellular distribution of focal adhesion kinase (FAK), consistent with altered cell adhesion dynamics. Notably, increased Cx46 expression in MCF-7 a breast cancer cell line and SK-Mel-2 melanoma cells reduces cell migration. Together, these findings uncover a novel Cx46–Src signaling axis that have the potential to induce focal adhesion remodeling and cell motility, providing new mechanistic insight into how Cxs regulate cancer cell migration independently of their canonical channel functions.