Transactivation of the PAR1-PAR2 Heterodimer by Thrombin Elicits β-Arrestin-mediated Endosomal Signaling

Lin, Huilan; Trejo, JoAnn

doi:10.1074/jbc.m112.439950

Cited by 81 publications

(92 citation statements)

References 47 publications

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“…Under these pathological conditions, PAR1 signaling switched from vascular disruptive to vascular protective as a consequence of increased endothelial PAR2 expression. Consistent with these studies, in cytokine-treated endothelial cells, expression of PAR2 enhanced the capacity of thrombin-activated PAR1 to signal differentially compared to PAR1 alone (135). Coimmunoprecipitation, fluorescence resonance energy transfer, and bioluminescence resonance energy transfer studies provide substantial evidence that PAR1 and PAR2 form a dimer (136).…”

Section: Par Dimerization and Drug Developmentsupporting

confidence: 55%

Challenges and Opportunities in Protease-Activated Receptor Drug Development

Hamilton

Trejo

2017

Annu. Rev. Pharmacol. Toxicol.

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Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging. As a consequence, researchers have taken a remarkable diversity of approaches to develop pharmacological entities that modulate PAR function. Here, we present an overview of the diversity of therapeutic agents that have been developed against PARs. We further discuss PAR biased signaling and the influence of receptor compartmentalization, posttranslational modifications, and dimerization, which are important considerations for drug development.

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Section: Par Dimerization and Drug Developmentsupporting

confidence: 55%

Challenges and Opportunities in Protease-Activated Receptor Drug Development

Hamilton

Trejo

2017

Annu. Rev. Pharmacol. Toxicol.

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“…The firststrand cDNA was amplified by PCR using primers specific for all conventional RGS mRNA transcripts. The RGS primer sequences and predicted PCR amplicon sizes have been described previously (24). The PCR amplification products were resolved by 1.8% (w/v) agarose gel electrophoresis and visualized by ethidium bromide staining.…”

Section: Methodsmentioning

confidence: 99%

Regulation of Protease-activated Receptor 1 Signaling by the Adaptor Protein Complex 2 and R4 Subfamily of Regulator of G Protein Signaling Proteins

Chen¹,

Siderovski

Neubig

et al. 2014

Journal of Biological Chemistry

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Background:The function of the clathrin adaptor AP-2 in the regulation of GPCR coupling to G protein signaling is not known. Results: AP-2 controls GPCR signaling by modulating receptor surface expression and, unexpectedly, through RGS protein recruitment to G proteins. Conclusion: AP-2 has diverse functions in the regulation of GPCR signaling. Significance: AP-2 provides a new mode of GPCR signal regulation.

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“…PAR2 expression is typically low in naïve endothelial cells and is increased following endothelial stimulation with inflammatory mediators . Intriguingly, the thrombin-cleaved PAR1-tethered ligand domain can bind intermolecularly and transactivate PAR2 (O'Brien et al, 2001), a situation that is favored when PAR2 expression is increased (Kaneider et al, 2007;Lin and Trejo, 2013). Thus, PARs can modulate each other's signaling activity by localizing thrombin to facilitate efficient receptor cleavage or by providing a tethered ligand domain to an adjacent PAR.…”

Section: Introductionmentioning

confidence: 99%