title: Novel mechanism regulating endothelial permeability via T-cadherin-dependent VE-cadherin phosphorylation and clathrin-mediated endocytosis.
abstract: T-cadherin is a unique member of the cadherin superfamily of adhesion molecules. In contrast to "classical" cadherins, T-cadherin lacks transmembrane and cytoplasmic domains and is anchored to the cell membrane via a glycosilphosphoinositol moiety. T-cadherin is predominantly expressed in cardiovascular system. Clinical and biochemical studies evidence that expression of T-cadherin increases in post-angioplasty restenosis and atherosclerotic lesions-conditions associated with endothelial dysfunction and pathological expression of adhesion molecules. Here, we provide data suggesting a new signaling mechanism by which T-cadherin regulates endothelial permeability. T-cadherin overexpression leads to VE-cadherin phosphorylation on Y731 (β-catenin-binding site), VE-cadherin clathrin-dependent endocytosis and its degradation in lysosomes. Moreover, T-cadherin overexpression results in activation of Rho GTPases signaling and actin stress fiber formation. Thus, T-cadherin up-regulation is involved in degradation of a key endothelial adhesion molecule, VE-cadherin, resulting in the disruption of endothelial barrier function. Our results point to the role of T-cadherin in regulation of endothelial permeability and its possible engagement in endothelial dysfunction.
authors.affiliation: Russian Cardiology Research-Industrial Complex, Ministry of Health, 3rd Cherepkovskaya St. 15a, 121552, Moscow, Russia.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Semina
authors.forename: Kseniya A
authors.initials: KA
authors.lastname: Rubina
authors.forename: Veronika Yu
authors.initials: VY
authors.lastname: Sysoeva
authors.forename: Pavel N
authors.initials: PN
authors.lastname: Rutkevich
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Kashirina
authors.forename: Vsevolod A
authors.initials: VA
authors.lastname: Tkachuk
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D022502:Stress Fibers / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000099152:Cadherin 5; C099972:H-cadherin; C066737:RHOA protein, human