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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Zhang, Y; Kontos, CD; Annex, BH; Popel, AS

Published Date

  • August 20, 2021

Published In

Volume / Issue

  • 7 / 1

Start / End Page

  • 34 -

PubMed ID

  • 34417472

Pubmed Central ID

  • PMC8379279

Electronic International Standard Serial Number (EISSN)

  • 2056-7189

Digital Object Identifier (DOI)

  • 10.1038/s41540-021-00194-6

Language

  • eng

Conference Location

  • England