PECAM‐1 supports leukocyte diapedesis by tension‐dependent dephosphorylation of VE‐cadherin

Leukocyte extravasation is an essential step during the immune response and requires the destabilization of endothelial junctions. We have shown previously that this process depends in vivo on the dephosphorylation of VE‐cadherin‐Y731. Here, we reveal the underlying mechanism. Leukocyte‐induced stimulation of PECAM‐1 triggers dissociation of the phosphatase SHP2 which then directly targets VE‐cadherin‐Y731. The binding site of PECAM‐1 for SHP2 is needed for VE‐cadherin dephosphorylation and subsequent endocytosis. Importantly, the contribution of PECAM‐1 to leukocyte diapedesis in vitro and in vivo was strictly dependent on the presence of Y731 of VE‐cadherin. In addition to SHP2, dephosphorylation of Y731 required Ca 2+ ‐signaling, non‐muscle myosin II activation, and endothelial cell tension. Since we found that β‐catenin/plakoglobin mask VE‐cadherin‐Y731 and leukocyte docking to endothelial cells exert force on the VE‐cadherin–catenin complex, we propose that leukocytes destabilize junctions by PECAM‐1‐SHP2‐triggered dephosphorylation of VE‐cadherin‐Y731 which becomes accessible by actomyosin‐mediated mechanical force exerted on the VE‐cadherin–catenin complex. SYNOPSIS The adhesion molecule PECAM‐1, known to mediate leukocyte migration across the blood vessel endothelium, is shown here to act by tension‐dependent VE‐cadherin dephosphorylation and internalization, which triggers the breach of endothelial junctions. PECAM‐1 promotes trans‐endothelial migration in vivo and in vitro by inducing SHP2‐mediated VE‐cadherin dephosphorylation at Tyr731. Release of SHP2 from PECAM‐1 is required for VE‐cadherin internalization upon leukocyte docking. VE‐cadherin dephosphorylation and internalization requires leukocyte‐induced Ca 2+ signals, actomyosin contraction, and endothelial cell tension. Leukocyte‐stimulated increase of mechanical forces induces unmasking of VE‐cadherin Tyr731 for dephosphorylation by SHP2. Graphical Abstract Trans‐endothelial migration of leukocytes requires the release of phosphatase SHP‐2 from PECAM‐1 to trigger mechanical force‐dependent modification of VE‐cadherin and opening of junctions.