Nectin receptors mediate mechanosensing to YAP via AKT

Cells are exposed to a variety of mechanical forces, including flow and stretch. Several transmembrane receptors have been implicated in mechanosignaling, but most cell-cell adhesion receptors have not been tested. Here, we use a siRNA screen targeting cell-cell junction-associated proteins to identify novel force-sensing receptors, measuring nuclear localization of the mechanosensitive transcription factor YAP. This screen identifies Nectin family cell-cell adhesion receptors as mechansensors. Of the Nectins, NECL5 depletion shows the lowest levels of YAP nuclear localization and reduces actin filament alignment. Nectin-3 (a known NECL5 interactor) also decreases YAP nuclear localization. In response to flow or stretch forces, NECL5 knockdown in endothelial cells reduces YAP signaling, acting through the PI3K/AKT pathway. NECL5 also mediates actin filament alignment induced by flow. Mechanical stimuli increase NECL5 localization to cell-cell junctions in vitro and in aortas in vivo. Together, these results indicate that the Nectin NECL5 plays a central role in mechanosignaling.