Abstract
VE-cadherin is an endothelial-specific transmembrane protein concentrated at cell-to-cell adherens junctions. Besides promoting cell adhesion and controlling vascular permeability, VE-cadherin transfers intracellular signals that contribute to vascular stabilization. However, the molecular mechanism by which VE-cadherin regulates vascular homoeostasis is still poorly understood. Here, we report that VE-cadherin expression and junctional clustering are required for optimal transforming growth factor-beta (TGF-beta) signalling in endothelial cells (ECs). TGF-beta antiproliferative and antimigratory responses are increased in the presence of VE-cadherin. ECs lacking VE-cadherin are less responsive to TGF-beta/ALK1- and TGF-beta/ALK5-induced Smad phosphorylation and target gene transcription. VE-cadherin coimmunoprecipitates with all the components of the TGF-beta receptor complex, TbetaRII, ALK1, ALK5 and endoglin. Clustered VE-cadherin recruits TbetaRII and may promote TGF-beta signalling by enhancing TbetaRII/TbetaRI assembly into an active receptor complex. Taken together, our data indicate that VE-cadherin is a positive and EC-specific regulator of TGF-beta signalling. This suggests that reduction or inactivation of VE-cadherin may contribute to progression of diseases where TGF-beta signalling is impaired.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type II / metabolism
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Allantois / cytology
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Allantois / drug effects
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Allantois / metabolism
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Animals
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Antigens, CD / metabolism*
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Cadherins / deficiency
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Cadherins / metabolism*
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Cell Movement / drug effects
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Proliferation / drug effects
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Dimerization
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Embryo, Mammalian / cytology
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Embryo, Mammalian / drug effects
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Embryo, Mammalian / metabolism
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Endothelial Cells / cytology
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Endothelial Cells / drug effects*
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Endothelial Cells / metabolism*
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Humans
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Kinetics
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Mice
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Models, Biological
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / drug effects*
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Smad2 Protein / metabolism
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Smad3 Protein / metabolism
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Transcription, Genetic / drug effects
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Transforming Growth Factor beta / pharmacology*
Substances
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Antigens, CD
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Cadherins
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Receptors, Transforming Growth Factor beta
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Smad2 Protein
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Smad3 Protein
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Transforming Growth Factor beta
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cadherin 5
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Protein Serine-Threonine Kinases
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ACVRL1 protein, human
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Activin Receptors, Type II
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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TGFBR1 protein, human
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Tgfbr1 protein, mouse