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

Konopa A, Meier M, Franz M, Bernardinelli E, Vögele AL, Atreya R, Ribback S, Roessler S, Aigner A, Singer K, Singer S, Sarikas A, Mühlich S (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Oncogenesis Nature Publishing Group

Book Volume: 11

Journal Issue: 1

DOI: 10.1038/s41389-022-00445-z

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.

Authors with CRIS profile

Andreas Konopa Professur für Molekulare und Klinische Pharmazie Melanie Meier Professur für Molekulare und Klinische Pharmazie Miriam Franz Professur für Molekulare und Klinische Pharmazie Anna-Lena Vögele Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen Susanne Mühlich Professur für Molekulare und Klinische Pharmazie

Involved external institutions

Universitätsklinikum Tübingen DE Germany (DE) Universität Greifswald DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Paracelsus Medizinische Privatuniversität AT Austria (AT) Universität Leipzig DE Germany (DE)

How to cite

APA:

Konopa, A., Meier, M., Franz, M., Bernardinelli, E., Vögele, A.-L., Atreya, R.,... Mühlich, S. (2022). 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. Oncogenesis, 11(1). https://doi.org/10.1038/s41389-022-00445-z

MLA:

Konopa, Andreas, et al. "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." Oncogenesis 11.1 (2022).

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