ArticleProceedings of the National Academy of Sciences of the United States of America2020
Phosphoproteomic analysis of protease-activated receptor-1 biased signaling reveals unique modulators of endothelial barrier function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
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Who cites it
26 citing papers in PubMed, 38 citations in OpenAlex.
- Phosphoproteomics in Vascular Biology and Disease: Illuminating Signaling in the Vessel.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Activated protein C drives β-arrestin-2- and c-Src-dependent phosphorylation of Cav1 and modulates Cav1 association with PAR1 and GRK5.The Journal of biological chemistry · 2026Article
- Activated Protein C and the Retina: From Physiology to Therapeutic Potential.International journal of molecular sciences · 2026Review
- From oversight to insight: the curious case of the endothelial insulin receptor.Blood vessels, thrombosis & hemostasis · 2026Review
- Kinome profiling: A veritable Rosetta Stone for protease-activated receptor 1 biased signaling.Vascular pharmacology · 2025Article
- In vivo neuroprotection in ischemic stroke by activated protein C requires β-arrestin 2.Blood vessels, thrombosis & hemostasis · 2025Article
- Endothelial protease-activated receptor 4: impotent or important?Frontiers in cardiovascular medicine · 2025Review
- Acetaminophen Overdose Reveals PAR4 as a Low-Expressing but Potent Receptor on the Hepatic Endothelium in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Japanese encephalitis virus-induced DNA methylation contributes to blood-brain barrier permeability by modulating tight junction protein expression.Journal of neuroinflammation · 2024Article
- Hemostasis and endothelial functionality: the double face of coagulation factors.Haematologica · 2024Review
- Acetaminophen Overdose Reveals Protease-Activated Receptor 4 as a Low-Expressing but Potent Receptor on the Hepatic Endothelium.bioRxiv : the preprint server for biology · 2024Article
- Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation.Biomedicines · 2023Review
- Fluorescence resonance energy transfer (FRET) spatiotemporal mapping of atypical P38 reveals an endosomal and cytosolic spatial bias.Scientific reports · 2023Article
- Subcellular location defines GPCR signal transduction.Science advances · 2023Article
- Phosphoproteomic Analysis of Dopamine D2 Receptor Signaling Reveals Interplay of G Protein- and β-Arrestin-Mediated Effects.Journal of proteome research · 2023Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Endothelial APC/PAR1 distinctly regulates cytokine-induced pro-inflammatory VCAM-1 expression.Frontiers in molecular biosciences · 2023Article
- Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model.Nature communications · 2022Article
- A "multi-omics" analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice.The Journal of experimental medicine · 2022Article
- Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C.The Journal of experimental medicine · 2022Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Thrombin, a procoagulant protease, cleaves and activates protease-activated receptor-1 (PAR1) to promote inflammatory responses and endothelial dysfunction. In contrast, activated protein C (APC), an anticoagulant protease, activates PAR1 through a distinct cleavage site and promotes anti-inflammatory responses, prosurvival, and endothelial barrier stabilization. The distinct tethered ligands formed through cleavage of PAR1 by thrombin versus APC result in unique active receptor conformations that bias PAR1 signaling. Despite progress in understanding PAR1 biased signaling, the proteins and pathways utilized by thrombin versus APC signaling to induce opposing cellular functions are largely unknown. Here, we report the global phosphoproteome induced by thrombin and APC signaling in endothelial cells with the quantification of 11,266 unique phosphopeptides using multiplexed quantitative mass spectrometry. Our results reveal unique dynamic phosphoproteome profiles of thrombin and APC signaling, an enrichment of associated biological functions, including key modulators of endothelial barrier function, regulators of gene transcription, and specific kinases predicted to mediate PAR1 biased signaling. Using small interfering RNA to deplete a subset of phosphorylated proteins not previously linked to thrombin or APC signaling, a function for afadin and adducin-1 actin binding proteins in thrombin-induced endothelial barrier disruption is unveiled. Afadin depletion resulted in enhanced thrombin-promoted barrier permeability, whereas adducin-1 depletion completely ablated thrombin-induced barrier disruption without compromising p38 signaling. However, loss of adducin-1 blocked APC-induced Akt signaling. These studies define distinct thrombin and APC dynamic signaling profiles and a rich array of proteins and biological pathways that engender PAR1 biased signaling in endothelial cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.