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

被引：34

作者：

Arif, Nida ^{[1
]}

Zinnhardt, Maren ^{[1
]}

Nyamay'Antu, Alengo ^{[1
]}

Teber, Denise ^{[1
]}

Brueckner, Randy ^{[1
]}

Schaefer, Kerstin ^{[1
]}

Li, Yu-Tung ^{[1
]}

Trappmann, Britta ^{[1
]}

Grashoff, Carsten ^{[2
]}

Vestweber, Dietmar ^{[1
]}

机构：

[1] Max Planck Inst Mol Biomed, Munster, Germany

[2] Univ Munster, Inst Mol Cell Biol, Munster, Germany

来源：

EMBO JOURNAL | 2021年 / 40卷 / 09期

关键词：

cell adhesion; endothelial junctions; leukocyte extravasation; mechanical tension; VE‐ cadherin; VASCULAR ENDOTHELIAL-CADHERIN; CELL-ADHESION MOLECULE-1; LIGHT-CHAIN KINASE; MEDIATES NEUTROPHIL TRANSMIGRATION; TYROSINE-PHOSPHATASE SHP-2; TRANSENDOTHELIAL MIGRATION; IN-VIVO; SEQUENTIAL ROLES; JAM-A; EXTRAVASATION;

D O I：

10.15252/embj.2020106113

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta-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.

引用

页数：20

共 75 条

[1] ICAM-1-mediated, Src- and Pyk2-dependent vascular endothelial cadherin tyrosine phosphorylation is required for leukocyte transendothelial migration [J].