Ion dependence of Na-K-ATPase-mediated epithelial cell adhesion and migration.

THE ROLE OF Na-K-ATPase in the regulation of epithelial cell polarity, adhesion, and migration has been demonstrated. Some of these processes, such as tight junction (TJ) formation, require ion transport function of Na-K-ATPase by its catalytic subunit Na-K. Other functions, such as motility suppression, cell adhesion, and contact inhibition, are mediated by the regulatory subunit Na-K, typically in association with NaKbut independent of the pump activity. Our recent study (5) showed that Na-Kcontrols cell migration and phosphatidylinositol 3-kinase (PI3K)/ERK signaling via Na/Ca exchanger 1 (NCX1)-mediated regulation of intracellular Ca concentration ([Ca ]i), highlighting the ion dependency of Na-Kmediated suppression of cell migration. Na-Kalso regulates membrane localization of other ion transporters, such as the large-conductance Ca -activated K (BKCa) channel and NaK-2Cl cotransporter isoform 2 (NKCC2). This leads us to speculate that these ion transporters might also be involved in facilitating additional functions of Na-K. In summary, we have come full circle: we started with the notion that the sole function of Na-K-ATPase is regulation of ion homeostasis, progressed to acceptance of the view that its subunit components can mediate diverse cellular processes by activating specific signaling pathways, independent of Na-K-ATPase activity, and, finally, closed the loop with recent studies that indicate that Na-Knot only regulates membrane localization and activity of Na-Kbut also of other ion transporters such as NCX1, BKCa, and NKCC2, thereby governing ion homeostasis in numerous ways. Here, we propose that ion homeostasis may be crucial for the multiple cell functions mediated by Na-K.