ArticleThe Journal of biological chemistry2016
Protease-activated Receptor-4 Signaling and Trafficking Is Regulated by the Clathrin Adaptor Protein Complex-2 Independent of β-Arrestins.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Mechanisms of Location Bias in G Protein-Coupled Receptors.Handbook of experimental pharmacology · 2026Review
- Numb-Associated Kinases-Mediated AP2M1 Activation Facilitates Porcine Reproductive and Respiratory Syndrome Virus Entry.Transboundary and emerging diseases · 2026Article
- AP5Z1 affects hepatocellular carcinoma growth and autophagy by regulating PTEN ubiquitination and modulating the PI3K/Akt/mTOR pathway.Journal of translational medicine · 2025Article
- Arrestin-independent internalization of the GLP-1 receptor is facilitated by a GRK, clathrin, and caveolae-dependent mechanism.The FEBS journal · 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
- SNX9 family mediates βarrestin-independent GPCR endocytosis.Communications biology · 2024Article
- 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
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Vascular Endothelial Cells Produce Coagulation Factors That Control Their Growth via Joint Protease-Activated Receptor and C5a Receptor 1 (CD88) Signaling.The American journal of pathology · 2022Article
- Differential regulation of G protein signaling inScience signaling · 2021Article
- The domino effect triggered by the tethered ligand of the protease activated receptors.Thrombosis research · 2020Review
- Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations.Cells · 2019Review
- Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions.Platelets · 2019Article
- Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.Thrombosis journal · 2019Review
- PAR4 overexpression promotes colorectal cancer cell proliferation and migration.Oncology letters · 2018Article
- GPCRs in Cancer: Protease-Activated Receptors, Endocytic Adaptors and Signaling.International journal of molecular sciences · 2018Review
- Protease-activated receptor-4 and purinergic receptor P2Y12 dimerize, co-internalize, and activate Akt signaling via endosomal recruitment of β-arrestin.The Journal of biological chemistry · 2017Article
- Endocytosis of tight junction proteins and the regulation of degradation and recycling.Annals of the New York Academy of Sciences · 2017Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Protease-activated receptor-4 (PAR4) is a G protein-coupled receptor (GPCR) for thrombin and is proteolytically activated, similar to the prototypical PAR1. Due to the irreversible activation of PAR1, receptor trafficking is intimately linked to signal regulation. However, unlike PAR1, the mechanisms that control PAR4 trafficking are not known. Here, we sought to define the mechanisms that control PAR4 trafficking and signaling. In HeLa cells depleted of clathrin by siRNA, activated PAR4 failed to internalize. Consistent with clathrin-mediated endocytosis, expression of a dynamin dominant-negative K44A mutant also blocked activated PAR4 internalization. However, unlike most GPCRs, PAR4 internalization occurred independently of β-arrestins and the receptor's C-tail domain. Rather, we discovered a highly conserved tyrosine-based motif in the third intracellular loop of PAR4 and found that the clathrin adaptor protein complex-2 (AP-2) is important for internalization. Depletion of AP-2 inhibited PAR4 internalization induced by agonist. In addition, mutation of the critical residues of the tyrosine-based motif disrupted agonist-induced PAR4 internalization. Using Dami megakaryocytic cells, we confirmed that AP-2 is required for agonist-induced internalization of endogenous PAR4. Moreover, inhibition of activated PAR4 internalization enhanced ERK1/2 signaling, whereas Akt signaling was markedly diminished. These findings indicate that activated PAR4 internalization requires AP-2 and a tyrosine-based motif and occurs independent of β-arrestins, unlike most classical GPCRs. Moreover, these findings are the first to show that internalization of activated PAR4 is linked to proper ERK1/2 and Akt activation.
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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.