The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index.
Autotaxin facilitates selective LPA receptor signaling
Open accessPublished version of a preprint
Abstract
Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA 1-3 ) and P2Y (LPA 4-6 ) G protein-coupled receptors. ATX/LPA promote several (patho)physiological processes, including in pulmonary fibrosis, thus serving as attractive drug targets. However, it remains unclear if clinical outcome depends on how different ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that inhibitors binding to the ATX “tunnel” specifically abrogate key aspects of ATX/LPA signaling. We find that the tunnel is essential for signaling efficacy and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. These responses are abrogated by tunnel-binding inhibitors, such as ziritaxestat, but not by inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.
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Lysophosphatidic acid, a simple phospholipid with myriad functions
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A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis
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Metadata
- Authors
- Salgado-Polo, F., Borza, R., Matsoukas, M.-T., Marsais, F., Jagerschmidt, C., Waeckel, L., Moolenaar, W. H., Ford, P., Heckmann, B., & Perrakis, A.
- Affiliations
- The Netherlands Cancer Institute (NL)
- University of West Attica (GR)
- Galapagos (France) (FR)
- Galapagos (Belgium) (BE)
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 30
- Issue
- 1
- Pages
- 69-84.e14
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- OpenAlex
- W4316036667
- Cited by
- 45
- References
- 70
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 13 · 2023: 7
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- Funders
- Engineering and Physical Sciences Research Council
- Swansea University
- Merck KGaA
- Universiteit Utrecht
- Ministerie van Volksgezondheid, Welzijn en Sport
- KWF Kankerbestrijding
- Galápagos
- Oncode Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- autotaxin, lysophosphatidic acid, LPA receptors, P2Y receptors, G protein-coupled receptor signaling, pulmonary fibrosis, radiation-induced pulmonary fibrosis, lung fibroblasts, receptor selectivity
- MeSH terms
- Animals, Fibroblasts, Lysophospholipids, Pulmonary Fibrosis, Signal Transduction, Receptors, Lysophosphatidic Acid, Mice
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