β‐catenin regulates FOXP2 transcriptional activity via multiple binding sites

Autor: Benjamin Bourgeois, Ernst Malle, Tianshu Gui, Peter Ulz, Gesa Richter, Boudewijn M.T. Burgering, Dirk von Lewinski, Chintan N. Koyani, Tobias Madl, Ellen Heitzer
Rok vydání: 2020
Předmět:
Models
Molecular
Protein Conformation
alpha-Helical
0301 basic medicine
Transcription
Genetic
Regulator
Biochemistry
0302 clinical medicine
Transcriptional regulation
Protein Isoforms
transcriptional regulation
Cloning
Molecular
Wnt Signaling Pathway
beta Catenin
Chemistry
Wnt signaling pathway
food and beverages
Gene Expression Regulation
Developmental
Forkhead Transcription Factors
Recombinant Proteins
Cell biology
030220 oncology & carcinogenesis
embryonic structures
β‐catenin
Original Article
signal transduction
Protein Binding
animal structures
FOXP2
Genetic Vectors
03 medical and health sciences
Cell Line
Tumor
Escherichia coli
Animals
Humans
Protein Interaction Domains and Motifs
Amino Acid Sequence
Binding site
Molecular Biology
Transcription factor
Binding Sites
Osteoblasts
Sequence Homology
Amino Acid
Gene Expression Profiling
C-terminus
fungi
RNA
Original Articles
Cell Biology
Embryo
Mammalian
intrinsically disordered protein
Wnt signaling
030104 developmental biology
Catenin
Protein Conformation
beta-Strand
Sequence Alignment
Zdroj: The Febs Journal
ISSN: 1742-4658
1742-464X
DOI: 10.1111/febs.15656
Popis: When the Wnt pathway is off duty, the transcription factor FOXP2 can up‐ and downregulate the transcription of a set of genes including Wnt‐related targets. Upon activation of the Wnt pathway, β‐catenin via direct interaction with FOXP2 can modulate its transcriptional activity in a TCF/LEF‐dependent and/or TCF/LEF‐independent manner.
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.
Databáze: OpenAIRE
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