Cited by 45Sphingolipid Metabolism and SignalingProtein Kinase Regulation and GTPase SignalingLipid metabolism and biosynthesis

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Autotaxin facilitates selective LPA receptor signaling

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Salgado-Polo, Fernando, Borza, Razvan, Matsoukas, Minos-Timotheos, Marsais, Florence, Jagerschmidt, Catherine, Waeckel, Ludovic, Moolenaar, Wouter H., Ford, Paul, Heckmann, Bertrand, Perrakis, Anastassis·2023·Cell Chemical Biology

DOI 10.1016/j.chembiol.2022.12.006

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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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A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis
Booijink, R. S., Salgado-Polo, F., Jamieson, C., Anastassis Perrakis, A., & Bansal, R. (2022) · EMBO Molecular Medicine · doi:10.15252/emmm.202216333 · Cited by 20
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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: Salgado-Polo, Fernando
Borza, Razvan
Matsoukas, Minos-Timotheos
Marsais, Florence
Jagerschmidt, Catherine
Moolenaar, Wouter H.
Perrakis, Anastassis
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
DOI: 10.1016/j.chembiol.2022.12.006
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
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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Autotaxin facilitates selective LPA receptor signaling

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