Article
- The EMBO Journal (2008) 27, 993 - 1004
- doi:10.1038/emboj.2008.46
Published online: 13 March 2008
Subject Categories:
VE-cadherin is a critical endothelial regulator of TGF-
signalling
Noemi Rudini1,7, Angelina Felici1,7, Costanza Giampietro1, MariaGrazia Lampugnani1,2, Monica Corada1, Kendra Swirsding1, Massimiliano Garrè1, Stefan Liebner3, Michelle Letarte4, Peter ten Dijke5 and Elisabetta Dejana1,2,6
- Vascular Biology Unit, FIRC Institute of Molecular Oncology, Milan, Italy
- Mario Negri Institute for Pharmacological Research, Milan, Italy
- Institute of Neurology, Medical School, University of Frankfurt/Main, Frankfurt, Germany
- Molecular Structure and Function Program, The Hospital for Sick Children, Heart and Stroke Richard Lewar Center of Excellence, University of Toronto, Toronto, Canada
- Molecular Cell Biology Department, Leiden University Medical Center, Leiden, The Netherlands
- Department of Biomolecular Sciences and Biotechnologies, School of Sciences, University of Milan, Milan, Italy
- These authors contributed equally to this work
Correspondence to:
Elisabetta Dejana, Vascular Biology Unit, FIRC Institute of Molecular Oncology, Via Adamello 16, Milan 20139, Italy. Tel.: +39 02 574303234; Fax: +39 02 574303244; E-mail: elisabetta.dejana@ifom-ieo-campus.it
Angelina Felici, FIRC Institute of Molecular Oncology, Via Adamello 16, Milan 20139, Italy. Tel.: +39 02 574303309; Fax: +39 02 574303244; E-mail: angelina.felici@ifom-ieo-campus.it
Received 27 August 2007; Accepted 20 February 2008
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-
(TGF-) signalling in endothelial cells (ECs). TGF- antiproliferative and antimigratory responses are increased in the presence of VE-cadherin. ECs lacking VE-cadherin are less responsive to TGF-/ALK1- and TGF-/ALK5-induced Smad phosphorylation and target gene transcription. VE-cadherin coimmunoprecipitates with all the components of the TGF- receptor complex, TRII, ALK1, ALK5 and endoglin. Clustered VE-cadherin recruits TRII and may promote TGF- signalling by enhancing TRII/TRI assembly into an active receptor complex. Taken together, our data indicate that VE-cadherin is a positive and EC-specific regulator of TGF- signalling. This suggests that reduction or inactivation of VE-cadherin may contribute to progression of diseases where TGF- signalling is impaired.
Keywords:
- endothelial cells,
- signal transduction,
- Smad,
- TGF-,
- VE-cadherin
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