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 α–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, β-catenin, and plakoglobin. Surprisingly, only plakoglobin but not β-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 β-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 β-catenin.

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

“…We found that the VEPTP promoter harbored 4 HREs, of which HRE2 showed the greatest HIF2α-dependent transctivation and was critical for VEPTP mRNA transcription. VE-PTP, an EC-specific transmembrane protein, forms a complex with VE-cadherin at AJs and is believed to mediate the assembly of AJs by VE-cadherin dephosphorylation (24). SRC kinase-dependent VE-cadherin phosphorylation (21) and VE-PTP-mediated dephosphorylation of VE-cadherin are important countervailing regulators of the remodeling and plasticity of AJs (31).…”

“…HIF2α-induced VE-PTP expression mediates AJ integrity through a reduction of VE-cadherin endocytosis. VE-PTP, through its interaction with VE-cadherin, regulates dephosphorylation of VE-cadherin (24), which is important in regulating VE-cadherin endocytosis-mediated internalization and hence determines the integrity of AJs (21,22). We therefore determined whether VE-PTP regulated VE-cadherin stability at AJs by modulating VE-cadherin internalization through an endocytotic mechanism.…”

“…Hence, VE-cadherin endocytosis functions as an important mechanism of AJ disassembly and increased endothelial permeability induced by inflammatory mediators (21,23). Recent studies have shown that the interaction between VE-cadherin and VE-PTP, an EC-specific transmembrane phosphatase and also a VE-cadherin binding partner, stabilizes VE-cadherin at AJs through dephosphorylation of tyrosine residues on VE-cadherin (24). Because little is known about the role of VE-PTP in regulating the assembly of AJs, in the present study, we addressed the relaVascular endothelial barrier dysfunction underlies diseases such as acute respiratory distress syndrome (ARDS), characterized by edema and inflammatory cell infiltration.…”

Dynamics between actin and the VE-cadherin/catenin complex

“…Furthermore, binding of certain leucocytes to endothelium dissociated the VE-PTP from VE-cadherin. 27 Another example is the transduction of mechanical stimulation into intracellular signals requiring VEGFR2, VE-cadherin, and PECAM-1. 28 Furthermore, VE-cadherin comprises a single membrane-spanning domain followed by a short carboxyterminal cytoplasmic domain that connects many regulatory molecules, including p120 ctn , β-, and γ-catenin.…”

Cellular players of hematopoietic stem cell mobilization in the bone marrow niche

“…In the BM, G-CSF-induced upregulation of sinusoidal endothelial CD26 (dipeptidyl peptidase 4) has been indicated to be important for HSPC transendothelial migration and mobilization via cleavage of full length neuropeptide Y (NPY) to NPY3-36 [79]. The in vivo effects of G-CSF on EC are also influenced by the involvement of infiltrated neutrophils and their secreted proangiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which leads to neovascularisation [80,81] and dissociation of tight junction element vascular endothelial cadherin (VE-cad) [82,83]. However, it must be noted that G-CSF treatment does not lead to measurable vascular leakage as determined by Evans Blue perfusion [84].…”