QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online December 20, 2007
doi: 10.1242/10.1242/jcs.022681

This Article Figures Only Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Turowski, P. Articles by Greenwood, J. Search for Related Content PubMed PubMed Citation Articles by Turowski, P. Articles by Greenwood, J. Social Bookmarking                         What's this?

Phosphorylation of vascular endothelial cadherin controls lymphocyte emigration

Patric Turowski^1,*, Roberta Martinelli¹, Rebecca Crawford^1,, David Wateridge^1,, Anna-Pia Papageorgiou¹, Maria Grazia Lampugnani², Alexander C. Gamp⁵, Dietmar Vestweber⁵, Peter Adamson^1,¶, Elisabetta Dejana^2,3,4 and John Greenwood^1,*

¹ Division of Cell Biology, Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
² Mario Negri Institute for Pharmacological Research, University of Milan, 20139 Milan, Italy
³ IFOM-IEO Campus, Via Adamello 16, University of Milan, 20139 Milan, Italy
⁴ Department of Biomolecular Sciences and Biotechnologies, Faculty of Sciences, University of Milan, 20139 Milan, Italy
⁵ Max-Planck-Institute of Molecular Biomedicine, Röntgenstr. 20, 48149 Münster, Germany

^* Authors for correspondence (e-mails: p.turowski{at}ucl.ac.uk; j.greenwood{at}ucl.ac.uk)

Accepted 25 September 2007

Summary

Lymphocytes emigrate from the circulation to target tissues through the microvascular endothelial cell (EC) barrier. During paracellular transmigration cell-cell junctions have been proposed to disengage and provide homophilic and heterophilic interaction surfaces in a zip-like process. However, it is not known whether ECs modulate junction proteins during this process. Here we show that tyrosine phosphorylation of adherens junction vascular endothelial cadherin (VEC) is required for successful transendothelial lymphocyte migration. We found that adhesion of lymphocytes or activation of the endothelial intercellular adhesion molecule 1 (ICAM1) led to tyrosine phosphorylation of VEC. Substitution of tyrosine for phenylalanine in VEC at positions 645, 731 or 733 produced ECs that were significantly less permissive to lymphocyte migration. We also found that these same tyrosine residues are involved in ICAM1-dependent changes of VEC phosphorylation. ICAM1 activation enhanced transendothelial permeability, suggesting the occurrence of junction disassembly. In agreement, the expression of VEC mutated at Y645F, Y731F or Y733F predominantly affected lymphocyte transmigration in paracellular areas. Taken together, these results demonstrate that phosphorylation of adherens junctions constitutes a molecular endpoint of lymphocyte-induced vascular EC signaling and may be exploited as a new target of anti-inflammatory therapies.

Key words: Lymphocyte migration, VE-cadherin, Tyrosine phosphorylation, Brain endothelium, ICAM1

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

Related articles in JCS:

ICAM, I saw, I crossed

JCS 2008 121: 105. [Full Text]  

This article has been cited by other articles:

				W. A. Muller Mechanisms of Transendothelial Migration of Leukocytes Circ. Res., July 31, 2009; 105(3): 223 - 230. [Abstract] [Full Text] [PDF]

				R. Martinelli, M. Gegg, R. Longbottom, P. Adamson, P. Turowski, and J. Greenwood ICAM-1-mediated Endothelial Nitric Oxide Synthase Activation via Calcium and AMP-activated Protein Kinase Is Required for Transendothelial Lymphocyte Migration Mol. Biol. Cell, February 1, 2009; 20(3): 995 - 1005. [Abstract] [Full Text] [PDF]

				A. F. Nottebaum, G. Cagna, M. Winderlich, A. C. Gamp, R. Linnepe, C. Polaschegg, K. Filippova, R. Lyck, B. Engelhardt, O. Kamenyeva, et al. VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF J. Exp. Med., November 24, 2008; 205(12): 2929 - 2945. [Abstract] [Full Text] [PDF]

				P. Alcaide, G. Newton, S. Auerbach, S. Sehrawat, T. N. Mayadas, D. E. Golan, P. Yacono, P. Vincent, A. Kowalczyk, and F. W. Luscinskas p120-Catenin regulates leukocyte transmigration through an effect on VE-cadherin phosphorylation Blood, October 1, 2008; 112(7): 2770 - 2779. [Abstract] [Full Text] [PDF]

				M. Stefanidakis, G. Newton, W. Y. Lee, C. A. Parkos, and F. W. Luscinskas Endothelial CD47 interaction with SIRP{gamma} is required for human T-cell transendothelial migration under shear flow conditions in vitro Blood, August 15, 2008; 112(4): 1280 - 1289. [Abstract] [Full Text] [PDF]

				E. Dejana, F. Orsenigo, and M. G. Lampugnani The role of adherens junctions and VE-cadherin in the control of vascular permeability J. Cell Sci., July 1, 2008; 121(13): 2115 - 2122. [Abstract] [Full Text] [PDF]