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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents



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ID: 744160.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN
Authors:Conway, D. E.; Coon, B. G.; Budatha, M.; Arsenovic, P. T.; Orsenigo, F.; Wessel, F.; Zhang, J.; Zhuang, Z.; Dejana, E.; Vestweber, D.; Schwartz, M. A.
Date of Publication (YYYY-MM-DD):2017-07-24
Title of Journal:Curr Biol
Volume:27
Issue / Number:14
Start Page:2219
End Page:2225 e2215
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Fluid shear stress due to blood flow on the vascular endothelium regulates blood vessel development, remodeling, physiology, and pathology [1, 2]. A complex consisting of PECAM-1, VE-cadherin, and vascular endothelial growth factor receptors (VEGFRs) that resides at endothelial cell-cell junctions transduces signals important for flow-dependent vasodilation, blood vessel remodeling, and atherosclerosis. PECAM-1 transduces forces to activate src family kinases (SFKs), which phosphorylate and transactivate VEGFRs [3-5]. By contrast, VE-cadherin functions as an adaptor that interacts with VEGFRs through their respective cytoplasmic domains and promotes VEGFR activation in flow [6]. Indeed, shear stress triggers rapid increases in force across PECAM-1 but decreases the force across VE-cadherin, in close association with downstream signaling [5]. Interestingly, VE-cadherin cytoplasmic tyrosine Y658 can be phosphorylated by SFKs [7], which is maximally induced by low shear stress in vitro and in vivo [8]. These considerations prompted us to address the involvement of VE-cadherin cytoplasmic tyrosines in flow sensing. We found that phosphorylation of a small pool of VE-cadherin on Y658 is essential for flow sensing through the junctional complex. Y658 phosphorylation induces dissociation of p120ctn, which allows binding of the polarity protein LGN. LGN is then required for multiple flow responses in vitro and in vivo, including activation of inflammatory signaling at regions of disturbed flow, and flow-dependent vascular remodeling. Thus, endothelial flow mechanotransduction through the junctional complex is mediated by a specific pool of VE-cadherin that is phosphorylated on Y658 and bound to LGN.
Free Keywords:Antigens, CD/*genetics/metabolism; Biomechanical Phenomena; Cadherins/*genetics/metabolism; Endothelium, Vascular/*physiology; Humans; Intercellular Junctions/metabolism; Intracellular Signaling Peptides and Proteins/*genetics/metabolism; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1/metabolism; Signal Transduction; Stress, Mechanical; VEGF receptor; flow signaling; mechanotransduction; p120 catenin; vascular biology
External Publication Status:published
Document Type:Article
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA. FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy. Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany. Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511, USA. FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Biotechnological and Biomolecular Sciences, School of Sciences, University of Milan, Via Celoria, 26, 20133 Milan, Italy. Department of Medicine (Cardiology), Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cell Biology, Yale University, New Haven, CT 06510, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06510, USA. Electronic address: martin.schwartz@yale.edu.
Identifiers:ISSN:1879-0445 (Electronic) 0960-9822 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28712573 [ID No:2]
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