Figure 9. Proposed model for the molecular mechanisms promoting opening of junctions during leukocyte diapedesis.

Leukocytes destabilize endothelial junctions by stimulating PECAM‐1. Leukocyte‐induced stimulation of PECAM‐1 triggers the release of SHP2 that directly interacts with and dephosphorylates VE‐cadherin‐Y731, which is required for the internalization of VE‐cadherin. In addition to mobilizing SHP2, leukocytes stimulate Ca²⁺‐signals in endothelial cells, and activate actomyosin‐based tension across the VE‐cadherin–catenin complex which is needed for Y731 dephosphorylation to occur. Since β‐catenin/plakoglobin mask the accessibility of Y731 for SHP2, 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.