Evidence map›Paper›PMID 41785085›Full record

ArticleCell reports2026

Signaling bias of the protease-activated receptor-1 is dictated by distinct GRK5 and β-arrestin-2 determinants.

Monica L Gonzalez Ramirez, Lennis B Orduña-Castillo, Carolyne Bardeleben, Huaping Qin, Ying Lin, Cierra A Birch, Irina Kufareva, JoAnn Trejo

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors.

Monica L Gonzalez RamirezDepartment of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Lennis B Orduña-CastilloDepartment of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Carolyne BardelebenDepartment of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Huaping QinDepartment of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Ying LinDepartment of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Cierra A BirchDepartment of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Irina KufarevaSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ikufareva@ucsd.edu.
JoAnn TrejoDepartment of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jotrejo@health.ucsd.edu.

Funding

UCSD/SDSU IRACDAK12GM068524 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI TREJO, JOANN · 2003 to 2025
$24.4M
Training In Cardiovascular Physiology & PharmacologyT32HL007444 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Ju Chen, Robert Scott Ross · 1985 to 2026
$11.1M
It's a tug of war: structure, consequences, and inhibition of CXCR4 and ACKR3 responses to lymphocyte chemoattractant CXCL12R01AI161880 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HANDEL, TRACY M, KUFAREVA, IRINA · 2021 to 2025
$3.4M
Endothelial Cytoprotective Signaling by Activated Protein C/Protease-activated Receptor-1R01HL163931 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Joann Trejo · 2023 to 2026
$2.7M
Spatiotemporally resolved architecture of G protein signaling downstream of CXCR4, the driver of lymphocyte migrationR21AI156662 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KUFAREVA, IRINA · 2021 to 2022
$434k
NHLBI NIH HHS R01 HL163931NHLBI NIH HHS T32 HL007444NIAID NIH HHS R01 AI161880NIAID NIH HHS R21 AI156662NIGMS NIH HHS K12 GM068524
6 · The paper itself

Abstract

G protein-coupled receptors (GPCRs) exhibit signaling bias or preferential activation of heterotrimeric G proteins versus GPCR kinase (GRK)-mediated β-arrestin signaling. The protease-activated receptor-1 (PAR1) activates both G protein and β-arrestin in response to thrombin but only β-arrestin in response to activated protein C (APC). Thrombin-activated PAR1-G protein signaling is desensitized by β-arrestin-1, whereas APC-activated PAR1 signaling is propagated by β-arrestin-2. The mechanisms underlying PAR1 biased signaling are not known. Here, using computational modeling combined with cellular and biochemical studies, we reveal the molecular basis of signaling by thrombin- and APC-activated PAR1. Although both thrombin- and APC-induced PAR1 signaling are regulated by the same GRK, GRK5, the two types of signaling are differentially dependent on GRK5 membrane anchoring, PAR1 C-terminal phosphorylation sites, and the binding mode of β-arrestin-2. These differences translate into distinct β-arrestin-2 conformations and define the APC cytoprotective signaling signature, which contrasts with thrombin inflammatory signaling.

Indexed as

beta-Arrestin 2G-Protein-Coupled Receptor Kinase 5Receptor, PAR-1Signal TransductionAnimalsHEK293 CellsHumansPhosphorylationProtein BindingProtein CThrombinbeta-Arrestin 2G-Protein-Coupled Receptor Kinase 5GRK5 protein, humanProtein CReceptor, PAR-1Thrombinactivated protein CAPCbiased agonistsbiased signalingCP: molecular biologyGPCRG proteinG protein-coupled receptorG protein-coupled receptor kinaseGRKPAR1phosphorylationthrombin

Identifiers

PMID41785085
PMCPMC13091039

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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.