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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 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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8379279 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Zhang Yu Y Kontos Christopher D CD Annex Brian H BH Popel Aleksander S AS

NPJ systems biology and applications 20210820 1

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 deve ...[more]

PMID: 34417472

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Project description:The mechanisms of the control and activity of the autophagy-lysosomal protein degradation machinery are emerging as an important theme for neurodevelopment and neurodegeneration. However, the underlying regulatory and functional networks of known genes controlling autophagy and lysosomal function and their role in disease are relatively unexplored. We performed a systems biology-based integrative computational analysis to study the interactions between molecular components and to develop models for regulation and function of genes involved in autophagy and lysosomal function. Specifically, we analyzed transcriptional and microRNA-based post-transcriptional regulation of these genes and performed functional enrichment analyses to understand their involvement in nervous system-related diseases and phenotypes. Transcriptional regulatory network analysis showed that binding sites for transcription factors, SREBP1, USF, AP-1 and NFE2, are common among autophagy and lysosomal genes. MicroRNA enrichment analysis revealed miR-130, 98, 124, 204 and 142 as the putative post-transcriptional regulators of the autophagy-lysosomal pathway genes. Pathway enrichment analyses revealed that the mTOR and insulin signaling pathways are important in the regulation of genes involved in autophagy. In addition, we found that glycosaminoglycan and glycosphingolipid pathways also make a major contribution to lysosomal gene regulation. The analysis confirmed the known contribution of the autophagy-lysosomal genes to Alzheimer and Parkinson diseases and also revealed potential involvement in tuberous sclerosis, neuronal ceroidlipofuscinoses, sepsis and lung, liver and prostatic neoplasms. To further probe the impact of autophagy-lysosomal gene deficits on neurologically-linked phenotypes, we also mined the mouse knockout phenotype data for the autophagylysosomal genes and found them to be highly predictive of nervous system dysfunction. Overall this study demonstrates the utility of systems biology-based approaches for understanding the autophagy-lysosomal pathways and gaining additional insights into the potential impact of defects in these complex biological processes.

Dataset Information

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

Publications

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

Similar Datasets

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