ArticleThe Journal of biological chemistry2008
Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
84 citing papers in PubMed, 150 citations in OpenAlex.
- Epithelial TMPRSS2 impairs glucose homeostasis in obese mice by regulating ghrelin-GLP-1 receptor signaling pathway.JCI insight · 2026Article
- Inhibition of protease-activated receptor-2 attenuates multi-walled carbon nanotube exacerbation of allergic lung disease in mice.Particle and fibre toxicology · 2025Article
- DNAJB2 Attenuates Rosacea Skin Inflammation and Angiogenesis by Inhibiting the Endoplasmic Reticulum Stress-mediated TLR2/Myd88/NF-κB pathway.Inflammation · 2025Article
- Article
- Selective Modulation of PAR-2-Driven Inflammatory Pathways by Oleocanthal: Attenuation of TNF-α and Calcium Dysregulation in Colorectal Cancer Models.International journal of molecular sciences · 2025Article
- Protease-activated receptor-2 (PAR2) mutation attenuates airway fibrosis in mice during the exacerbation of house dust mite‑induced allergic lung disease by multi‑walled carbon nanotubes.Respiratory research · 2025Article
- Activation of the Coagulation Cascade as a Universal Danger Sign.Current issues in molecular biology · 2025Review
- Multifactorial Causes and Consequences of TLSP Production, Function, and Release in the Asthmatic Airway.Biomolecules · 2024Review
- Methadone Requires the Co-Activation of μ-Opioid and Toll-Like-4 Receptors to Produce Extracellular DNA Traps in Bone-Marrow-Derived Mast Cells.International journal of molecular sciences · 2024Article
- Platelet-activating factor and protease-activated receptor 2 cooperate to promote neutrophil recruitment and lung inflammation through nuclear factor-kappa B transactivation.Scientific reports · 2023Article
- Cooperation of Complement MASP-1 with Other Proinflammatory Factors to Enhance the Activation of Endothelial Cells.International journal of molecular sciences · 2023Article
- Computational modeling of TGF-β2:TβRI:TβRII receptor complex assembly as mediated by the TGF-β coreceptor betaglycan.Biophysical journal · 2023Article
- Review
- Lacrimal Gland Epithelial Cells Shape Immune Responses through the Modulation of Inflammasomes and Lipid Metabolism.International journal of molecular sciences · 2023Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Diversification of PAR signaling through receptor crosstalk.Cellular & molecular biology letters · 2022Review
- Advocacy of targeting protease-activated receptors in severe coronavirus disease 2019.British journal of pharmacology · 2022Article
- Protease-activated receptor 2 enhances innate and inflammatory mechanisms induced by lipopolysaccharide in macrophages from C57BL/6 mice.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Article
- Downregulation of Matriptase Inhibits Porphyromonas gingivalis Lipopolysaccharide-Induced Matrix Metalloproteinase-1 and Proinflammatory Cytokines by Suppressing the TLR4/NF-BioMed research international · 2022Article
- Article
24 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Proteinase-activated receptor 2 (PAR2), a seven-transmembrane G protein-coupled receptor, is activated at inflammatory sites by proteolytic cleavage of its extracellular N terminus by trypsin-like enzymes, exposing a tethered, receptor-activating ligand. Synthetic agonist peptides (AP) that share the tethered ligand sequence also activate PAR2, often measured by Ca2+ release. PAR2 contributes to inflammation through activation of NF-kappaB-regulated genes; however, the mechanism by which this occurs is unknown. Overexpression of human PAR2 in HEK293T cells resulted in concentration-dependent, PAR2 AP-inducible NF-kappaB reporter activation that was protein synthesis-independent, yet blocked by inhibitors that uncouple Gi proteins or sequester intracellular Ca2+. Because previous studies described synergistic PAR2- and TLR4-mediated cytokine production, we hypothesized that PAR2 and TLR4 might interact at the level of signaling. In the absence of TLR4, PAR2-induced NF-kappaB activity was inhibited by dominant negative (DN)-TRIF or DN-TRAM constructs, but not by DN-MyD88, findings confirmed using cell-permeable, adapter-specific BB loop blocking peptides. Co-expression of TLR4/MD-2/CD14 with PAR2 in HEK293T cells led to a synergistic increase in AP-induced NF-kappaB signaling that was MyD88-dependent and required a functional TLR4, despite the fact that AP exhibited no TLR4 agonist activity. Co-immunoprecipitation of PAR2 and TLR4 revealed a physical association that was AP-dependent. The response to AP or lipopolysaccharide was significantly diminished in TLR4(-/-) and PAR2(-/-) macrophages, respectively, and SW620 colonic epithelial cells exhibited synergistic responses to co-stimulation with AP and lipopolysaccharide. Our data suggest a unique interaction between two distinct innate immune response receptors and support a novel paradigm of receptor cooperativity in inflammatory responses.
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What OpenQuestion holds
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.