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Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap

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posted on 2017-07-10, 14:22 authored by Deborah O. A. Alawo, Tariq A. Tahir, Marlies Fischer, Declan G. Bates, Svetlana R. Amirova, Nicholas P. J. Brindle
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.

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Citation

Scientific Reports, 2017, 7, Article number: 3658

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

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  • VoR (Version of Record)

Published in

Scientific Reports

Publisher

Nature Publishing Group

issn

2045-2322

Acceptance date

2017-05-08

Copyright date

2017

Available date

2017-07-10

Publisher version

https://www.nature.com/articles/s41598-017-03981-6

Language

en

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