Cell adhesion is a crucial step in proliferation, differentiation, migration, apoptosis, and metastasis. In previous works we have shown that cell adhesion is modulated by ouabain, a highly specific inhibitor of Na+,K+-ATPase, recently found to be a hormone. In the present work we pursue the investigation of the effect of ouabain on a special type of cell-cell interaction: the rescue of ouabain-sensitive MDCK cells (W) by ouabain-resistant cells (R). In cultured monolayers of pure W cells, ouabain triggers the "P-->A mechanism" (from pump/adhesion) consisting of a cascade of phosphorylations that retrieves adhesion-associated molecules occludin and beta-catenin and results in detachment of the cell. When W cells are instead cocultured with R cells, the P-->A reaction is blocked, and W cells are rescued. Furthermore, in these R/W cocultures ouabain promotes cell-cell communication by means of gap junctions by specifically enhancing the expression of connexin 32 and addressing this molecule to the plasma membrane. Ouabain also promotes the internalization of the beta-subunit of the Na+,K+-ATPase. These observations open the possibility that the crucial processes mentioned at the beginning would be under the control of the hormone ouabain.