β-catenin regulates FOXP2 transcriptional activity via multiple binding sites.

Autor: Richter G; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria., Gui T; Oncode Institute and Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, The Netherlands., Bourgeois B; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria., Koyani CN; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria.; Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Austria., Ulz P; Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Austria., Heitzer E; Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Austria., von Lewinski D; Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Austria., Burgering BMT; Oncode Institute and Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, The Netherlands., Malle E; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria., Madl T; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria.; BioTechMed, Graz, Austria.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2021 May; Vol. 288 (10), pp. 3261-3284. Date of Electronic Publication: 2020 Dec 26.
DOI: 10.1111/febs.15656
Abstrakt: The transcription factor forkhead box protein P2 (FOXP2) is a highly conserved key regulator of embryonal development. The molecular mechanisms of how FOXP2 regulates embryonal development, however, remain elusive. Using RNA sequencing, we identified the Wnt signaling pathway as key target of FOXP2-dependent transcriptional regulation. Using cell-based assays, we show that FOXP2 transcriptional activity is regulated by the Wnt coregulator β-catenin and that β-catenin contacts multiple regions within FOXP2. Using nuclear magnetic resonance spectroscopy, we uncovered the molecular details of these interactions. β-catenin contacts a disordered FOXP2 region with α-helical propensity via its folded armadillo domain, whereas the intrinsically disordered β-catenin N terminus and C terminus bind to the conserved FOXP2 DNA-binding domain. Using RNA sequencing, we confirmed that β-catenin indeed regulates transcriptional activity of FOXP2 and that the FOXP2 α-helical motif acts as a key regulatory element of FOXP2 transcriptional activity. Taken together, our findings provide first insight into novel regulatory interactions and help to understand the intricate mechanisms of FOXP2 function and (mis)-regulation in embryonal development and human diseases. DATABASE: Expression data are available in the GEO database under the accession number GSE138938.
(© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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