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.
Journal
Oncogenesis
ISSN: 2157-9024
Titre abrégé: Oncogenesis
Pays: United States
ID NLM: 101580004
Informations de publication
Date de publication:
28 Dec 2022
28 Dec 2022
Historique:
received:
07
07
2022
accepted:
15
12
2022
revised:
12
12
2022
entrez:
28
12
2022
pubmed:
29
12
2022
medline:
29
12
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36577757
doi: 10.1038/s41389-022-00445-z
pii: 10.1038/s41389-022-00445-z
pmc: PMC9797565
doi:
Types de publication
Journal Article
Langues
eng
Pagination
69Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : GRK1910
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : MU2737/2-4
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : GRK1910
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : MU 2737/2-2
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : MU2737/2.4
Informations de copyright
© 2022. The Author(s).
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