Leukocyte extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin.
Tyrosine phosphorylation of the adhesion molecule VE-cadherin is assumed to affect endothelial junction integrity. However, it remains unclear whether tyrosine residues of VE-cadherin are required for the induction of vascular permeability and the regulation of leukocyte extravasation in vivo. We found here that knock-in mice expressing a Y685F mutant of VE-cadherin had impaired induction of vascular permeability, but those expressing a Y731F mutant did not. In contrast, mice expressing the Y731F VE-cadherin mutant showed decreased neutrophil-extravasation in cremaster tissue, but those expressing the Y685F mutant did not. Whereas inflammatory mediators induced the phosphorylation of Tyr685 in vivo, Tyr731 showed high baseline phosphorylation. Leukocytes triggered dephosphorylation of Tyr731 via the tyrosine phosphatase SHP-2, which allowed the adaptin AP-2 to bind and initiate endocytosis of VE-cadherin. Thus, Tyr685 and Tyr731 of VE-cadherin distinctly and selectively regulate the induction of vascular permeability or leukocyte extravasation.
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Florian
F
Wessel
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Mark
M
Winderlich
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Maren
M
Holm
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Maike
M
Frye
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Ronmy
R
Rivera-Galdos
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Matthias
M
Vockel
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Ruth
R
Linnepe
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Ute
U
Ipe
Department of Anesthesiology and Critical Care Medicine, University of Münster, Germany.
Anika
A
Stadtmann
1] Max-Planck-Institute for Molecular Biomedicine, Münster, Germany. [2] Department of Anesthesiology and Critical Care Medicine, University of Münster, Germany.
Alexander
A
Zarbock
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Astrid F
AF
Nottebaum
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
Dietmar
D
Vestweber
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D001558:Benzethonium / Q000031:analogs & derivatives; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D014443:Tyrosine / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D001558:Benzethonium; D015820:Cadherins; D014443:Tyrosine; D000099152:Cadherin 5; C005106:methylbenzethonium chloride