Systematic identification of p11 as a signaling modulator across the GPCRome
8 affiliations
- 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
- 2Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
- 3Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY, USA.
- 4Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA.
- 5Department of Medicine Solna, Division of Immunology and Respiratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
- 6Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
- 7Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
- 8Basic and Clinical Neuroscience, King’s College London, London, UK.
Abstract
) is a ubiquitously expressed molecular scaffold that is known to be required for behavioral responses to certain antidepressants, presumably through its effect on G protein-coupled receptor (GPCR)-mediated signaling. Here, we demonstrate that p11 recruitment to GPCRs is promoted by an active receptor conformation. Furthermore, by mapping the GPCR-p11 interactome using a multiplexed suspension bead array (SBA) of 211 receptors, we identified more than two dozen high-confidence physical interactors across diverse GPCR signaling families. We define the functional significance of these interactions by focusing on a novel SBA screening hit, the protease-activated receptor 2 (PAR2). Transcriptomic fingerprinting and signaling assays in p11-knockout cells reveal that p11 acts as an amplifier of endogenous PAR2 signaling. PAR2 and p11 are specifically coexpressed in vivo in a subset of sensory neurons, and p11-deficient mice exhibit a blunted PAR2-mediated inflammatory response. Our results establish p11 as a widespread, activity-dependent modulator of GPCR-mediated signaling outcomes across diverse physiological processes.
Related
- GPCR-PTM: an interpretable, topology-aware rule-based framework for residue-level post-translational modification annotation and prediction across the human GPCRome
- The Endogenous Negative Allosteric Modulator, Lynx1, Inhibits Nicotinic Cholinergic Signaling in the Ventral Tegmental Area to Regulate Nicotine Reinforcement
- In Silico and Experimental Evidence for Theasaponin E2 as a Modulator of the AKT1/GSK-3β Signaling Axis in Osteoclast Differentiation
- RiboBA: a bias-aware probabilistic framework for robust ORF identification across diverse ribosome profiling protocols
- Identification of a Conserved Temporal Molecular Response Signature to CDK4/6 Inhibition Through Multi-Omics Integration Across Cancer Cell Lines
BibTeX
@article{saarinen2026systematic,
title = {{Systematic identification of p11 as a signaling modulator across the GPCRome}},
author = {Marcus Saarinen and Ilana B. Kotliar and Inga Höffkes and Niclas Branzell and Carl-Fredrik Bowin and Leo Dahl and Elisa Da Silva and Vassilis Glaros and Alonso Abney and Annika Bendes and Taras Kreslavsky and Jochen M. Schwenk and Thomas P. Sakmar and Per Svenningsson},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeg6567},
url = {https://www.science.org/doi/10.1126/sciadv.aeg6567},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systematic identification of p11 as a signaling modulator across the GPCRome
AU - Marcus Saarinen
AU - Ilana B. Kotliar
AU - Inga Höffkes
AU - Niclas Branzell
AU - Carl-Fredrik Bowin
AU - Leo Dahl
AU - Elisa Da Silva
AU - Vassilis Glaros
AU - Alonso Abney
AU - Annika Bendes
AU - Taras Kreslavsky
AU - Jochen M. Schwenk
AU - Thomas P. Sakmar
AU - Per Svenningsson
PY - 2026
DA - 2026/10/02
JO - Science Advances
DO - 10.1126/sciadv.aeg6567
UR - https://www.science.org/doi/10.1126/sciadv.aeg6567
AB - ) is a ubiquitously expressed molecular scaffold that is known to be required for behavioral responses to certain antidepressants, presumably through its effect on G protein-coupled receptor (GPCR)-mediated signaling. Here, we demonstrate that p11 recruitment to GPCRs is promoted by an active receptor conformation. Furthermore, by mapping the GPCR-p11 interactome using a multiplexed suspension bead array (SBA) of 211 receptors, we identified more than two dozen high-confidence physical interactors across diverse GPCR signaling families. We define the functional significance of these interactions by focusing on a novel SBA screening hit, the protease-activated receptor 2 (PAR2). Transcriptomic fingerprinting and signaling assays in p11-knockout cells reveal that p11 acts as an amplifier of endogenous PAR2 signaling. PAR2 and p11 are specifically coexpressed in vivo in a subset of sensory neurons, and p11-deficient mice exhibit a blunted PAR2-mediated inflammatory response. Our results establish p11 as a widespread, activity-dependent modulator of GPCR-mediated signaling outcomes across diverse physiological processes.
SN - 2375-2548
ER -