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

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 (sTi...

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Autores principales:	Deborah O. A. Alawo, Tariq A. Tahir, Marlies Fischer, Declan G. Bates, Svetlana R. Amirova, Nicholas P. J. Brindle
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d67adf71f1c94acdaa76476210bf82b7
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spelling	oai:doaj.org-article:d67adf71f1c94acdaa76476210bf82b72021-12-02T11:52:16ZRegulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap10.1038/s41598-017-03981-62045-2322https://doaj.org/article/d67adf71f1c94acdaa76476210bf82b72017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03981-6https://doaj.org/toc/2045-2322Abstract 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.Deborah O. A. AlawoTariq A. TahirMarlies FischerDeclan G. BatesSvetlana R. AmirovaNicholas P. J. BrindleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Deborah O. A. Alawo Tariq A. Tahir Marlies Fischer Declan G. Bates Svetlana R. Amirova Nicholas P. J. Brindle Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap
description	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.
format	article
author	Deborah O. A. Alawo Tariq A. Tahir Marlies Fischer Declan G. Bates Svetlana R. Amirova Nicholas P. J. Brindle
author_facet	Deborah O. A. Alawo Tariq A. Tahir Marlies Fischer Declan G. Bates Svetlana R. Amirova Nicholas P. J. Brindle
author_sort	Deborah O. A. Alawo
title	Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap
title_short	Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap
title_full	Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap
title_fullStr	Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap
title_full_unstemmed	Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap
title_sort	regulation of angiopoietin signalling by soluble tie2 ectodomain and engineered ligand trap
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d67adf71f1c94acdaa76476210bf82b7
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Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap

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