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http://purl.uniprot.org/citations/27304216http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27304216http://www.w3.org/2000/01/rdf-schema#comment"

Background

Fibulin-5 is an extracellular matrix glycoprotein that plays critical roles in vasculogenesis and embryonic development. Deletion of Fibulin-5 in mice results in enhanced skin vascularization and upregulation of the angiogenesis factor angiopoietin-1 (Ang-1), suggesting that Fibulin-5 functions as an angiogenesis inhibitor. In this study, we investigate the inhibitory effects of Fibulin-5 on Ang-1/TIE-2 receptor pathway signaling and cell survival in human endothelial cells.

Methodology/principal findings

Recombinant wild-type and RGE-mutant Fibulin-5 proteins were generated through stable transfection of HEK293 and CHO cells, respectively. In vitro solid phase binding assays using pure proteins revealed that wild-type Fibulin-5 does not bind to Ang-1 or TIE-2 proteins but strongly binds to heparin. Binding assays using human umbilical vein endothelial cells (HUVECs) indicated that wild-type Fibulin-5 strongly binds to cells but RGE-mutant Fibulin-5, which is incapable of binding to integrins, does not. Pre-incubation of HUVECs for 1 hr with Fibulin-5 significantly increased caspase 3/7 activity, ERK1/2 phosphorylation, and expressions of the transcription factor early growth response 1 (EGR1) and the dual-specificity phosphatase 5 (DUSP5). Fibulin-5 also strongly attenuated Ang-1-induced TIE-2 and AKT phosphorylation, decreased Ang-1-induced expressions of the transcription factors Inhibitor of DNA Binding 1 (ID1) and Kruppel-like Factor 2 (KLF2), and reversed the inhibitory effect of Ang-1 on serum deprivation-induced cytotoxicity and caspase 3/7 activity.

Conclusion/significance

We conclude that Fibulin-5 strongly binds to the endothelial cell surface through heparin-sulfate proteoglycans and possibly integrins and that it exerts strong anti-angiogenic effects by reducing endothelial cell viability and interfering with the signaling pathways of the Ang-1/TIE-2 receptor axis."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.org/dc/terms/identifier"doi:10.1371/journal.pone.0156994"xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/author"Sanchez V."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/author"Chan W."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/author"Davis E.C."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/author"Tiedemann K."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/author"Ismail H."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/author"Hussain S.N."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/author"Mayaki D."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/name"PLoS One"xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/pages"e0156994"xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/title"Fibulin-5 Regulates Angiopoietin-1/Tie-2 Receptor Signaling in Endothelial Cells."xsd:string
http://purl.uniprot.org/citations/27304216http://purl.uniprot.org/core/volume"11"xsd:string
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