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PMID: 18337748 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

VE-cadherin is a critical endothelial regulator of TGF-beta signalling.

The EMBO journal ·Vol. 27 ·No. 7 ·2008-04-09 ·Pages 993-1004

Rudini N, Felici A, Giampietro C, Lampugnani M, Corada M, Swirsding K, Garrè M, Liebner S, Letarte M, ten Dijke P, Dejana E

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.

MeSH Terms
Activin Receptors, Type II/metabolism Allantois/cytology,drug effects,metabolism Animals Antigens, CD/metabolism Cadherins/deficiency,metabolism Cell Movement/drug effects Cell Nucleus/drug effects,metabolism Cell Proliferation/drug effects Dimerization Embryo, Mammalian/cytology,drug effects,metabolism Endothelial Cells/cytology,drug effects,metabolism Humans Kinetics Mice Models, Biological Phosphorylation/drug effects Protein Binding/drug effects Protein Serine-Threonine Kinases/metabolism Receptor, Transforming Growth Factor-beta Type I Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/metabolism Signal Transduction/drug effects Smad2 Protein/metabolism Smad3 Protein/metabolism Transcription, Genetic/drug effects Transforming Growth Factor beta/pharmacology
Chemicals
Antigens, CD Cadherins Receptors, Transforming Growth Factor beta Smad2 Protein Smad3 Protein Transforming Growth Factor beta cadherin 5 Protein Serine-Threonine Kinases ACVRL1 protein, human Activin Receptors, Type II Receptor, Transforming Growth Factor-beta Type I Receptor, Transforming Growth Factor-beta Type II TGFBR1 protein, human Tgfbr1 protein, mouse
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Rudini Noemi
Vascular Biology Unit, FIRC Institute of Molecular Oncology, Milan, Italy.
Felici Angelina
Giampietro Costanza
Lampugnani MariaGrazia
Corada Monica
Swirsding Kendra
Garrè Massimiliano
Liebner Stefan
Letarte Michelle
ten Dijke Peter
Dejana Elisabetta
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2008.46
Published
2008-04-09
Epub
2008-00-13
Pages
993-1004
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2323269
Subset
IM
External Links
PubMed source DOI: 10.1038/emboj.2008.46 PMC Full Text View journal details
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