Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation.
Wnt growth factors mediate cell fate determination during embryogenesis and in the renewal of tissues in the adult. Wnts act by stabilizing cellular levels of the transcriptional coactivator beta-catenin, which forms complexes with sequence-specific DNA-binding Tcf/Lef transcription factors. In the absence of nuclear beta-catenin, Tcf/Lefs act as transcriptional repressors by binding to Groucho/TLE proteins. The molecular basis of the switch from transcriptional repression to activation during Wnt signaling has not been clear, in particular whether factors other than beta-catenin are required to disrupt the interaction between Groucho/TLE and Tcf/Lef. Using highly purified proteins, we demonstrate that beta-catenin displaces Groucho/TLE from Tcf/Lef by binding to a previously unidentified second, low-affinity binding site on Lef-1 that includes sequences just N-terminal to the DNA-binding domain, and that overlaps the Groucho/TLE-binding site.
Daniels
Danette L
DL
Department of Structural Biology, Stanford University School of Medicine, Stanford University School of Medicine, 299 Campus Drive West, Stanford, California 94305-5126, USA.
Weis
William I
WI
D000818:Animals; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics*; D051153:Wnt Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D010446:Peptide Fragments; D012097:Repressor Proteins; C499043:TLE1 protein, human; C434946:Tle1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D004247:DNA