Phosphorylation of Vascular Endothelial Cadherin Controls Lymphocyte Emigration
| Autor: | David Wateridge, Peter Adamson, Roberta Martinelli, Dietmar Vestweber, Alexander C. Gamp, Anna-Pia Papageorgiou, Rebecca Crawford, John Greenwood, Elisabetta Dejana, Patric Turowski, Maria Grazia Lampugnani |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Beta-catenin
Intercellular Adhesion Molecule-1 Molecular Sequence Data CHO Cells Biology Article Permeability Cell Line Adherens junction chemistry.chemical_compound Mice Cricetulus Cell Movement Cricetinae Animals Amino Acid Sequence Lymphocytes Phosphorylation Protein Structure Quaternary Conserved Sequence ICAM-1 Cadherin Tyrosine phosphorylation Cell Biology Adherens Junctions Cadherins Phosphoproteins Protocadherins Cell biology Protein Structure Tertiary Rats chemistry Amino Acid Substitution Mutagenesis biology.protein Tyrosine Endothelium Vascular VE-cadherin Sequence Alignment |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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