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Regulation of angiopoietin signalling by soluble Tie2 ectodomain and engineered ligand trap

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Alawo, Deborah O. A., Tahir, Tariq A., Fischer, Marlies, Bates, Declan, Amirova, Svetlana R. and Brindle, Nicholas P. J. (2017) Regulation of angiopoietin signalling by soluble Tie2 ectodomain and engineered ligand trap. Scientific Reports, 7 (1). 3658. doi:10.1038/s41598-017-03981-6 ISSN 2045-2322.

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Official URL: http://dx.doi.org/10.1038/s41598-017-03981-6

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Abstract

Angiopoietin-1 (Angpt1) is a glycoprotein ligand important for maintaining the vascular system. It signals via a receptor tyrosine kinase expressed on the surface on endothelial cells, Tie2. This receptor can undergo regulated ectodomain cleavage that releases the ligand-binding domain (sTie2) into the circulation. The concentration of sTie2 is increased in a range of conditions, including peripheral arterial disease and myocardial infarction, where it has been suggested to bind and block Angpt1 resulting in vascular dysfunction. Here we use a joint mathematical modelling and experimental approach to assess the potential impact of sTie2 on the ability of Angpt1 to signal. We find that the concentrations of sTie2 relative to Angpt1 required to suppress signalling by the ligand are more than ten-fold higher than those ever seen in normal or disease conditions. In contrast to the endogenous sTie2, an engineered form of sTie2, which presents dimeric ligand binding sites, inhibits Angpt1 signalling at seventy-fold lower concentrations. While loss of Tie2 ectodomain can suppress Angpt1 signalling locally in the cells in which the receptor is lost, our study shows that the resulting increase in circulating sTie2 is unlikely to affect Angpt1 activity elsewhere in the body.

Item Type: Journal Article
Subjects: Q Science > QM Human anatomy
Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Engineering > Engineering
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Glycoproteins, Blood-vessels, Protein-tyrosine kinase
Journal or Publication Title: Scientific Reports
Publisher: Nature Publishing Group
ISSN: 2045-2322
Official Date: 16 June 2017
Dates:
DateEvent
16 June 2017Published
8 May 2017Accepted
Volume: 7
Number: 1
Article Number: 3658
DOI: 10.1038/s41598-017-03981-6
Status: Peer Reviewed
Publication Status: Published
Reuse Statement (publisher, data, author rights): ** From Europe PMC via Jisc Publications Router. ** Licence for this article: cc by
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 17 August 2017
Date of first compliant Open Access: 17 August 2017
Funder: British Heart Foundation
Grant number: PG/11/26/28838, PG/13/43/30312

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