title: VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF.
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.
authors.affiliation: Max-Planck-Institute of Molecular Biomedicine, Münster, Germany.
authors.forename: Astrid F
authors.initials: AF
authors.lastname: Nottebaum
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cagna
authors.forename: Mark
authors.initials: M
authors.lastname: Winderlich
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Gamp
authors.forename: Ruth
authors.initials: R
authors.lastname: Linnepe
authors.forename: Christian
authors.initials: C
authors.lastname: Polaschegg
authors.forename: Kristina
authors.initials: K
authors.lastname: Filippova
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Olena
authors.initials: O
authors.lastname: Kamenyeva
authors.forename: Maria Gabriele
authors.initials: MG
authors.lastname: Bixel
authors.forename: Stefan
authors.initials: S
authors.lastname: Butz
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D015815:Cell Adhesion Molecules; D034741:RNA, Small Interfering; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D051185:gamma Catenin; D000099152:Cadherin 5