ZFIN ID: ZDB-PUB-130712-20
GRG5/AES Interacts with T-Cell Factor 4 (TCF4) and Downregulates Wnt Signaling in Human Cells and Zebrafish Embryos
Costa, A.M., Pereira-Castro, I., Ricardo, E., Spencer, F., Fisher, S., and da Costa, L.T.
Date: 2013
Source: PLoS One   8(7): e67694 (Journal)
Registered Authors: Fisher, Shannon
Keywords: none
MeSH Terms:
  • Amino Acid Motifs
  • Animals
  • Co-Repressor Proteins/genetics
  • Co-Repressor Proteins/metabolism*
  • Down-Regulation
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Humans
  • Protein Interaction Maps
  • Repressor Proteins/genetics
  • Repressor Proteins/metabolism*
  • Signal Transduction
  • Transcription Factor 7-Like 2 Protein/chemistry
  • Transcription Factor 7-Like 2 Protein/genetics
  • Transcription Factor 7-Like 2 Protein/metabolism*
  • Transcriptional Activation*
  • Up-Regulation
  • Wnt Proteins/genetics
  • Wnt Proteins/metabolism*
  • Zebrafish/embryology*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • beta Catenin/genetics
  • beta Catenin/metabolism
PubMed: 23840876 Full text @ PLoS One
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ABSTRACT

Transcriptional control by TCF/LEF proteins is crucial in key developmental processes such as embryo polarity, tissue architecture and cell fate determination. TCFs associate with β-catenin to activate transcription in the presence of Wnt signaling, but in its absence act as repressors together with Groucho-family proteins (GRGs). TCF4 is critical in vertebrate intestinal epithelium, where TCF4-β-catenin complexes are necessary for the maintenance of a proliferative compartment, and their abnormal formation initiates tumorigenesis. However, the extent of TCF4-GRG complexes’ roles in development and the mechanisms by which they repress transcription are not completely understood. Here we characterize the interaction between TCF4 and GRG5/AES, a Groucho family member whose functional relationship with TCFs has been controversial. We map the core GRG interaction region in TCF4 to a 111-amino acid fragment and show that, in contrast to other GRGs, GRG5/AES-binding specifically depends on a 4-amino acid motif (LVPQ) present only in TCF3 and some TCF4 isoforms. We further demonstrate that GRG5/AES represses Wnt-mediated transcription both in human cells and zebrafish embryos. Importantly, we provide the first evidence of an inherent repressive function of GRG5/AES in dorsal-ventral patterning during early zebrafish embryogenesis. These results improve our understanding of TCF-GRG interactions, have significant implications for models of transcriptional repression by TCF-GRG complexes, and lay the groundwork for in depth direct assessment of the potential role of Groucho-family proteins in both normal and abnormal development.

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