LPA receptor 1 (LPAR1) is a novel interaction partner of Filamin A that promotes Filamin A phosphorylation, MRTF-A transcriptional activity and oncogene-induced senescence
Andreas Konopa,
Melanie A. Meier,
Miriam J. Franz,
Emanuele Bernardinelli,
Anna-Lena Voegele,
Raja Atreya,
Silvia Ribback,
Stephanie Roessler,
Achim Aigner,
Kerstin Singer,
Stephan Singer,
Antonio Sarikas,
Susanne Muehlich
Affiliations
Andreas Konopa
Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg
Melanie A. Meier
Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg
Miriam J. Franz
Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg
Emanuele Bernardinelli
Institute of Pharmacology and Toxicology, Paracelsus Medical University
Anna-Lena Voegele
Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg
Raja Atreya
Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg
Silvia Ribback
Institute of Pathology, University of Greifswald
Stephanie Roessler
Institute of Pathology, University of Heidelberg
Achim Aigner
Rudolf Boehm Institute of Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig
Kerstin Singer
Department for Pathology, University Hospital Tuebingen
Stephan Singer
Department for Pathology, University Hospital Tuebingen
Antonio Sarikas
Institute of Pharmacology and Toxicology, Paracelsus Medical University
Susanne Muehlich
Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg
Abstract Myocardin-related transcription factors A and B (MRTFs) are coactivators of Serum Response Factor (SRF), which controls fundamental biological processes such as cell growth, migration, and differentiation. MRTF and SRF transcriptional activity play an important role in hepatocellular carcinoma (HCC) growth, which represents the second leading cause of cancer-related mortality in humans worldwide. We, therefore, searched for druggable targets in HCC that regulate MRTF/SRF transcriptional activity and can be exploited therapeutically for HCC therapy. We identified the G protein-coupled lysophosphatidic acid receptor 1 (LPAR1) as a novel interaction partner of MRTF-A and Filamin A (FLNA) using fluorescence resonance energy transfer-(FRET) and proximity ligation assay (PLA) in vitro in HCC cells and in vivo in organoids. We found that LPAR1 promotes FLNA phosphorylation at S2152 which enhances the complex formation of FLNA and MRTF-A, actin polymerization, and MRTF transcriptional activity. Pharmacological blockade or depletion of LPAR1 prevents FLNA phosphorylation and complex formation with MRTF-A, resulting in reduced MRTF/SRF target gene expression and oncogene-induced senescence. Thus, inhibition of the LPAR1–FLNA–MRTF-A interaction represents a promising strategy for HCC therapy.