ArticleThe Journal of biological chemistry2017
Protease-activated receptor-4 and purinergic receptor P2Y12 dimerize, co-internalize, and activate Akt signaling via endosomal recruitment of β-arrestin.
Article in The Journal of biological chemistry, 2017. 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, 44 citations in OpenAlex.
- The Na/K-ATPase α1 subunit fine-tunes platelet P2Y12 function and mediates sex dimorphism-associated thrombosis.Blood advances · 2026Article
- Dabigatran Attenuates the Binding of Thrombin to Platelets-A Novel Mechanism of Action.Thrombosis and haemostasis · 2025Article
- Species Differences in Platelet Protease-Activated Receptors.International journal of molecular sciences · 2023Review
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- The Molecular Aspects of Disturbed Platelet Activation through ADP/P2YInternational journal of molecular sciences · 2021Article
- Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clearScience translational medicine · 2021Article
- That was then, this is now: the development of our knowledge and understanding of P2 receptor subtypes.Purinergic signalling · 2021Article
- Protease-activated receptors: An illustrated review.Research and practice in thrombosis and haemostasis · 2021Review
- Article
- Interclass GPCR heteromerization affects localization and trafficking.Science signaling · 2020Article
- Article
- Lodoxamide Attenuates Hepatic Fibrosis in Mice: Involvement of GPR35Biomolecules & therapeutics · 2020Article
- Down-regulation of platelet adhesion receptors is a controlling mechanism of thrombosis, while also affecting post-transfusion efficacy of stored platelets.Thrombosis journal · 2019Review
- Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.Thrombosis journal · 2019Review
- The protease-activated receptor 4 Ala120Thr variant alters platelet responsiveness to low-dose thrombin and protease-activated receptor 4 desensitization, and is blocked by non-competitive P2YJournal of thrombosis and haemostasis : JTH · 2018Article
- Endocytosis is required for CThe Journal of biological chemistry · 2018Article
- GPCRs in Cancer: Protease-Activated Receptors, Endocytic Adaptors and Signaling.International journal of molecular sciences · 2018Review
- PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke.Blood · 2018Article
- The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein-coupled receptor lysosomal sorting and signaling.The Journal of biological chemistry · 2018Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Vascular inflammation and thrombosis require the concerted actions of several different agonists, many of which act on G protein-coupled receptors (GPCRs). GPCR dimerization is a well-established phenomenon that can alter protomer function. In platelets and other cell types, protease-activated receptor-4 (PAR4) has been shown to dimerize with the purinergic receptor P2Y12 to coordinate β-arrestin-mediated Akt signaling, an important mediator of integrin activation. However, the mechanism by which the PAR4-P2Y12 dimer controls β-arrestin-dependent Akt signaling is not known. We now report that PAR4 and P2Y12 heterodimer internalization is required for β-arrestin recruitment to endosomes and Akt signaling. Using bioluminescence resonance energy transfer, immunofluorescence microscopy, and co-immunoprecipitation in cells expressing receptors exogenously and endogenously, we demonstrate that PAR4 and P2Y12 specifically interact and form dimers expressed at the cell surface. We also found that activation of PAR4 but not of P2Y12 drives internalization of the PAR4-P2Y12 heterodimer. Remarkably, activated PAR4 internalization was required for recruitment of β-arrestin to endocytic vesicles, which was dependent on co-expression of P2Y12. Interestingly, stimulation of the PAR4-P2Y12 heterodimer promotes β-arrestin and Akt co-localization to intracellular vesicles. Moreover, activated PAR4-P2Y12 internalization is required for sustained Akt activation. Thus, internalization of the PAR4-P2Y12 heterodimer is necessary for β-arrestin recruitment to endosomes and Akt signaling and lays the foundation for examining whether blockade of PAR4 internalization reduces integrin and platelet activation.
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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.