PECAM-1 supports leukocyte diapedesis by tension-dependent dephosphorylation of VE-cadherin
| Autor: | Denise Teber, Carsten Grashoff, Dietmar Vestweber, Yu-Tung Li, Randy Brückner, Alengo Nyamay’Antu, Nida Arif, Kerstin Schaefer, Maren Zinnhardt, Britta Trappmann |
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| Rok vydání: | 2021 |
| Předmět: |
Plakoglobin
Protein Tyrosine Phosphatase Non-Receptor Type 11 Biology Endocytosis General Biochemistry Genetics and Molecular Biology Dephosphorylation 03 medical and health sciences Mice 0302 clinical medicine Antigens CD Myosin Human Umbilical Vein Endothelial Cells Leukocytes Animals Humans Calcium Signaling Gene Knock-In Techniques Phosphorylation Cell adhesion Molecular Biology 030304 developmental biology 0303 health sciences General Immunology and Microbiology General Neuroscience Transendothelial and Transepithelial Migration Actomyosin Cadherins Leukocyte extravasation Cell biology Endothelial stem cell Platelet Endothelial Cell Adhesion Molecule-1 Tyrosine VE-cadherin 030217 neurology & neurosurgery |
| Zdroj: | The EMBO journal. 40(9) |
| ISSN: | 1460-2075 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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