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.

Autor: Konopa A; Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Meier MA; Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Franz MJ; Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Bernardinelli E; Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria., Voegele AL; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Atreya R; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Ribback S; Institute of Pathology, University of Greifswald, Greifswald, Germany., Roessler S; Institute of Pathology, University of Heidelberg, Heidelberg, Germany., Aigner A; Rudolf Boehm Institute of Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany., Singer K; Department for Pathology, University Hospital Tuebingen, 72076, Tuebingen, Germany., Singer S; Department for Pathology, University Hospital Tuebingen, 72076, Tuebingen, Germany., Sarikas A; Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria., Muehlich S; Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. susanne.muehlich@fau.de.
Jazyk: angličtina
Zdroj: Oncogenesis [Oncogenesis] 2022 Dec 28; Vol. 11 (1), pp. 69. Date of Electronic Publication: 2022 Dec 28.
DOI: 10.1038/s41389-022-00445-z
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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