1. VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF.
- Author
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Nottebaum AF, Cagna G, Winderlich M, Gamp AC, Linnepe R, Polaschegg C, Filippova K, Lyck R, Engelhardt B, Kamenyeva O, Bixel MG, Butz S, and Vestweber D
- Subjects
- Animals, Antigens, CD genetics, Cadherins genetics, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Cell Line, Endosomes metabolism, Endothelial Cells cytology, Humans, Intercellular Junctions metabolism, Leukocytes cytology, Lymphocytes cytology, Lymphocytes metabolism, Mice, Neutrophils cytology, Neutrophils metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 3 genetics, Tumor Necrosis Factor-alpha metabolism, beta Catenin metabolism, gamma Catenin genetics, Antigens, CD metabolism, Cadherins metabolism, Endothelial Cells metabolism, Endothelium cytology, Endothelium metabolism, Leukocytes metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 3 metabolism, Vascular Endothelial Growth Factor A metabolism, gamma Catenin metabolism
- Abstract
We have shown recently that vascular endothelial protein tyrosine phosphatase (VE-PTP), an endothelial-specific membrane protein, associates with vascular endothelial (VE)-cadherin and enhances VE-cadherin function in transfected cells (Nawroth, R., G. Poell, A. Ranft, U. Samulowitz, G. Fachinger, M. Golding, D.T. Shima, U. Deutsch, and D. Vestweber. 2002. EMBO J. 21:4885-4895). We show that VE-PTP is indeed required for endothelial cell contact integrity, because down-regulation of its expression enhanced endothelial cell permeability, augmented leukocyte transmigration, and inhibited VE-cadherin-mediated adhesion. Binding of neutrophils as well as lymphocytes to endothelial cells triggered rapid (5 min) dissociation of VE-PTP from VE-cadherin. This dissociation was only seen with tumor necrosis factor alpha-activated, but not resting, endothelial cells. Besides leukocytes, vascular endothelial growth factor also rapidly dissociated VE-PTP from VE-cadherin, indicative of a more general role of VE-PTP in the regulation of endothelial cell contacts. Dissociation of VE-PTP and VE-cadherin in endothelial cells was accompanied by tyrosine phoshorylation of VE-cadherin, beta-catenin, and plakoglobin. Surprisingly, only plakoglobin but not beta-catenin was necessary for VE-PTP to support VE-cadherin adhesion in endothelial cells. In addition, inhibiting the expression of VE-PTP preferentially increased tyrosine phosphorylation of plakoglobin but not beta-catenin. In conclusion, leukocytes interacting with endothelial cells rapidly dissociate VE-PTP from VE-cadherin, weakening endothelial cell contacts via a mechanism that requires plakoglobin but not beta-catenin.
- Published
- 2008
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