VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF.
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.
Nottebaum
Astrid F
AF
Max-Planck-Institute of Molecular Biomedicine, Münster, Germany.
Cagna
Giuseppe
G
Winderlich
Mark
M
Gamp
Alexander C
AC
Linnepe
Ruth
R
Polaschegg
Christian
C
Filippova
Kristina
K
Lyck
Ruth
R
Engelhardt
Britta
B
Kamenyeva
Olena
O
Bixel
Maria Gabriele
MG
Butz
Stefan
S
Vestweber
Dietmar
D
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
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