A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway

Abstract The Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The un...

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Autores principales:	Yu Zhang, Christopher D. Kontos, Brian H. Annex, Aleksander S. Popel
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b76836dc5cf64ade854948acc776b695
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spelling	oai:doaj.org-article:b76836dc5cf64ade854948acc776b6952021-12-02T18:51:40ZA systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway10.1038/s41540-021-00194-62056-7189https://doaj.org/article/b76836dc5cf64ade854948acc776b6952021-08-01T00:00:00Zhttps://doi.org/10.1038/s41540-021-00194-6https://doaj.org/toc/2056-7189Abstract The Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.Yu ZhangChristopher D. KontosBrian H. AnnexAleksander S. PopelNature PortfolioarticleBiology (General)QH301-705.5ENnpj Systems Biology and Applications, Vol 7, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Yu Zhang Christopher D. Kontos Brian H. Annex Aleksander S. Popel A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway
description	Abstract The Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.
format	article
author	Yu Zhang Christopher D. Kontos Brian H. Annex Aleksander S. Popel
author_facet	Yu Zhang Christopher D. Kontos Brian H. Annex Aleksander S. Popel
author_sort	Yu Zhang
title	A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway
title_short	A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway
title_full	A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway
title_fullStr	A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway
title_full_unstemmed	A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway
title_sort	systems biology model of junctional localization and downstream signaling of the ang–tie signaling pathway
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b76836dc5cf64ade854948acc776b695
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A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway

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