Faculty Opinions recommendation of PECAM-1 supports leukocyte diapedesis by tension-dependent dephosphorylation of VE-cadherin.
Year: 2021
Type: peer-review
Abstract: 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 Ca2+ -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.© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license. PMID: 33604918 Funding information This work was supported by: Deutsche Forschungsgemeinschaft (DFG), Grant ID: SFB1009,A01 Deutsche Forschungsgemeinschaft (DFG), Grant ID: SFB1348 (B01),B01
Author: William A Muller
Institution: Northwestern University
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4241832782