Evidence map›Paper›PMID 42827708›Full record

ArticleiScience2026

Non-canonical cleavage of GPR125/ADGRA3 releases extracellular receptor fragments detectable in cerebrospinal fluid.

Anna L S Walser, Olav Larsen, Chiara Stüdle, Nicoline Wichmand Thorsen, Florian Seufert, Anna Katarzyna Drzazga, Renata Mężyk-Kopeć, Isha Raj, Filippa Liliendahl Qvist, Sofie Morsing Bagger and 23 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in iScience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

33 authors.

Anna L S WalserLaboratory of Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Olav LarsenLaboratory of Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Chiara StüdleTheodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
Nicoline Wichmand ThorsenDepartment of Biomedical Sciences, Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.
Florian SeufertInstitute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, 04103 Leipzig, Germany.
Anna Katarzyna DrzazgaLaboratory of Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Renata Mężyk-KopećFaculty of Biochemistry, Biophysics and Biotechnology, the Jagiellonian University in Kraków, 30-387 Kraków, Poland.
Isha RajNovo Nordisk Foundation Center for Protein Research, ICMM, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Filippa Liliendahl QvistDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen Ø, Denmark.
Sofie Morsing BaggerLaboratory of Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Gertrud Malene HjortøLaboratory of Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Trine Toft-BertelsenDepartment of Neuroscience, University of Copenhagen, 2200 Copenhagen N, Denmark.
Emily SlowikowskiLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
Silvia BergtLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
Eva GansemanLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
Christoffer Knak GothLaboratory of Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Juliane LokauInstitute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany.
Christoph GarbersInstitute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany.
Hiroshi IshikawaLaboratory of Clinical Regenerative Medicine, Department of Neurosurgery, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Horst SchrotenPediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Paul ProostLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
Anja Hviid SimonsenDanish Dementia Research Centre, Copenhagen University Hospital - Rigshospitalet, 2100 Copenhagen N, Denmark.
Nicholas M I TaylorNovo Nordisk Foundation Center for Protein Research, ICMM, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Joanna BeretaFaculty of Biochemistry, Biophysics and Biotechnology, the Jagiellonian University in Kraków, 30-387 Kraków, Poland.
Nanna MacAulayNovo Nordisk Foundation Center for Protein Research, ICMM, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Peter W HildebrandDepartment of Biomedical Sciences, Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.
Niels Henning SkotteDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen Ø, Denmark.
Katja SpiessLaboratory of Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Tobias LangenhanRudolf Schӧnheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany.
Michael J DaviesDepartment of Biomedical Sciences, Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.
Britta EngelhardtTheodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
Pedro E MarquesLaboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
Mette M RosenkildeLaboratory of Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Adhesion G protein-coupled receptors (aGPCRs) are crucial for barrier tissues and typically autoproteolytically cleaved into N- and C-terminal fragments (NTF and CTF) that remain non-covalently associated until separation is triggered. Here, we show that human GPR125 (ADGRA3), expressed in choroid plexus epithelium, is not cleaved at the GPCR autoproteolysis site (GPS), consistent with its divergent SLS motif. Instead, it undergoes non-canonical proteolytic processing that generates and releases atypical, non-canonical N-terminal fragments (ncNTFs), a process further enhanced by insulin. Using mutational analyses, metalloprotease inhibition, and ADAM10/17-deficient cells, we find that multiple proteases likely participate in cleavage. Mass spectrometry reveals one specific cleavage site, and real-time imaging uncovers GPR125's intracellular trafficking and shedding dynamics. Changing the GPS destabilizes the ncNTF-ncCTF association and increases ncNTF release, thereby promoting cell viability. Finally, detection of multiple GPR125-derived peptides in human cerebrospinal fluid suggests ncNTF shedding

Indexed as

ADGRA3adhesion G protein-coupled receptorscerebrospinal fluidcleavageGPCRGPR125N-terminal fragmentshedding

Identifiers

PMID42827708
PMCPMC13631675

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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 Socratic graph.