Simple SummaryExternal and internal mechanical forces affect the shape, movement, proliferation and metabolism of cells within tissues. The transcriptional regulators YAP and TAZ are key sensors of mechanical inputs, and their aberrant activation in solid tumors promotes cancer aggressiveness. It is thus important to understand how YAP/TAZ activity is controlled, and how such control is altered in tumors. DAB2IP is a cytoplasmic protein that negatively modulates several signaling pathways; being a tumor suppressor, it is frequently disabled in cancer. Using mammary epithelial cells as a model, we find that DAB2IP levels depend on cell density, and depletion of DAB2IP modifies cell morphology and stiffness in confluent cultures. We also find that DAB2IP behaves as an inhibitor of YAP/TAZ nuclear localization and activity in confluent cells. These observations suggest that DAB2IP may function as a sensor of cellular interactions, contributing to restraining the activation of oncogenic signaling pathways in intact tissues.AbstractExternal and internal mechanical forces modulate cell morphology, movement, proliferation and metabolism, and represent crucial inputs for tissue homeostasis. The transcriptional regulators YAP and TAZ are important effectors of mechanical signaling and are frequently activated in solid tumors, correlating with metastasis, chemoresistance, and shorter patient survival. YAP/TAZ activity is controlled by various pathways that sense cell shape, polarity, contacts, and mechanical tension. In tumors, aberrant YAP/TAZ activation may result from cancer-related alterations of such regulatory networks. The tumor suppressor DAB2IP is a Ras-GAP and scaffold protein that negatively modulates multiple oncogenic pathways and is frequently downregulated or inactivated in solid tumors. Here, we provide evidence that DAB2IP expression is sustained by cell confluency. We also find that DAB2IP depletion in confluent cells alters their morphology, reducing cell packing while increasing cell stiffness. Finally, we find that DAB2IP depletion in confluent cells favors YAP/TAZ nuclear localization and transcriptional activity, while its ectopic expression in subconfluent cells increases YAP/TAZ retention in the cytoplasm. Together, these data suggest that DAB2IP may function as a sensor of cell interactions, contributing to dampening cellular responses to oncogenic inputs in confluent cells and that DAB2IP loss-of-function would facilitate YAP/TAZ activation in intact epithelia, accelerating oncogenic transformation.