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Publication : Phosphorylation of vascular endothelial cadherin controls lymphocyte emigration.

First Author  Turowski P Year  2008
Journal  J Cell Sci Volume  121
Issue  Pt 1 Pages  29-37
PubMed ID  18096689 Mgi Jnum  J:130883
Mgi Id  MGI:3772504 Doi  10.1242/jcs.022681
Citation  Turowski P, et al. (2008) Phosphorylation of vascular endothelial cadherin controls lymphocyte emigration. J Cell Sci 121(Pt 1):29-37
abstractText  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.
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