ArticleThe Journal of biological chemistry2012
Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4).
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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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
28 citing papers in PubMed, 44 citations in OpenAlex.
- Mechanisms of XCR1 Membrane Trafficking and Constitutive Endocytosis.Basic & clinical pharmacology & toxicology · 2026Article
- GPCR signaling via cAMP nanodomains.The Biochemical journal · 2025Review
- Endothelial protease-activated receptor 4: impotent or important?Frontiers in cardiovascular medicine · 2025Review
- Modulating GPCR and 14-3-3 protein interactions: Prospects for CNS drug discovery.Drug discovery today · 2023Review
- Protease-Activated Receptor 2 Controls Vascular Smooth Muscle Cell Proliferation in Cyclic AMP-Dependent Protein Kinase/Mitogen-Activated Protein Kinase Kinase 1/2-Dependent Manner.Journal of vascular research · 2023Article
- Diversification of PAR signaling through receptor crosstalk.Cellular & molecular biology letters · 2022Review
- Review
- Protease Activated Receptors and Arthritis.International journal of molecular sciences · 2021Review
- Compartmentalized GPCR Signaling from Intracellular Membranes.The Journal of membrane biology · 2021Review
- The Small GTPase RAC1B: A Potent Negative Regulator of-and Useful Tool to Study-TGFβ Signaling.Cancers · 2020Review
- Dual RXR motifs regulate nerve growth factor-mediated intracellular retention of the delta opioid receptor.Molecular biology of the cell · 2019Article
- Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.Thrombosis journal · 2019Review
- Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer.International journal of molecular sciences · 2018Review
- Protease-Activated Receptor 4 (PAR4): A Promising Target for Antiplatelet Therapy.International journal of molecular sciences · 2018Review
- Proteinase-Activated Receptor 2 May Drive Cancer Progression by Facilitating TGF-β Signaling.International journal of molecular sciences · 2017Review
- Protease-activated receptor 4: from structure to function and back again.British journal of pharmacology · 2016Review
- Acid-Sensing Ion Channel 2a (ASIC2a) Promotes Surface Trafficking of ASIC2b via Heteromeric Assembly.Scientific reports · 2016Article
- GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper.Molecular psychiatry · 2016Article
- Rare platelet GPCR variants: what can we learn?British journal of pharmacology · 2015Review
- Minireview: Role of intracellular scaffolding proteins in the regulation of endocrine G protein-coupled receptor signaling.Molecular endocrinology (Baltimore, Md.) · 2015Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
Abstract
Proteinase-activated receptors 4 (PAR(4)) is a class A G protein-coupled receptor (GPCR) recognized through the ability of serine proteases such as thrombin and trypsin to mediate receptor activation. Due to the irreversible nature of activation, a fresh supply of receptor is required to be mobilized to the cell surface for responsiveness to agonist to be sustained. Unlike other PAR subtypes, the mechanisms regulating receptor trafficking of PAR(4) remain unknown. Here, we report novel features of the intracellular trafficking of PAR(4) to the plasma membrane. PAR(4) was poorly expressed at the plasma membrane and largely retained in the endoplasmic reticulum (ER) in a complex with the COPI protein subunit β-COP1. Analysis of the PAR(4) protein sequence identified an arginine-based (RXR) ER retention sequence located within intracellular loop-2 (R(183)AR → A(183)AA), mutation of which allowed efficient membrane delivery of PAR(4). Interestingly, co-expression with PAR(2) facilitated plasma membrane delivery of PAR(4), an effect produced through disruption of β-COP1 binding and facilitation of interaction with the chaperone protein 14-3-3ζ. Intermolecular FRET studies confirmed heterodimerization between PAR(2) and PAR(4). PAR(2) also enhanced glycosylation of PAR(4) and activation of PAR(4) signaling. Our results identify a novel regulatory role for PAR(2) in the anterograde traffic of PAR(4). PAR(2) was shown to both facilitate and abrogate protein interactions with PAR(4), impacting upon receptor localization and cell signal transduction. This work is likely to impact markedly upon the understanding of the receptor pharmacology of PAR(4) in normal physiology and disease.
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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.