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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-08-01
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| Series: | npj Systems Biology and Applications |
| Online Access: | https://doi.org/10.1038/s41540-021-00194-6 |
| _version_ | 1818856036943003648 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T08:18:07Z |
| format | Article |
| id | doaj.art-b76836dc5cf64ade854948acc776b695 |
| institution | Directory Open Access Journal |
| issn | 2056-7189 |
| language | English |
| last_indexed | 2024-12-19T08:18:07Z |
| publishDate | 2021-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Systems Biology and Applications |
| spelling | doaj.art-b76836dc5cf64ade854948acc776b6952022-12-21T20:29:27ZengNature Portfolionpj Systems Biology and Applications2056-71892021-08-017111010.1038/s41540-021-00194-6A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathwayYu Zhang0Christopher D. Kontos1Brian H. Annex2Aleksander S. Popel3Department of Biomedical Engineering, School of Medicine, Johns Hopkins UniversityDepartment of Medicine, Division of Cardiology, Duke University Medical CenterDepartment of Medicine and the Vascular Biology Center, Medical College of Georgia at Augusta UniversityDepartment of Biomedical Engineering, School of Medicine, Johns Hopkins UniversityAbstract 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.https://doi.org/10.1038/s41540-021-00194-6 |
| spellingShingle | 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 npj Systems Biology and Applications |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41540-021-00194-6 |
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