TCF7 (TCF1), LEF1, TCF7L1 (TCF3) and TCF7L2 (TCF4) are HMG box-containing DNA-binding proteins that recognize WNT-responsive elements (WREs) in the promoters of WNT target genes. The WRE consensus sequence is CCTTTGWW, where W represents either T or A (reviewed in Brantjes et al, 2002). In the absence of a WNT signal, promoter-bound TCF/LEF is bound by one of four Groucho homologues, TLE1, 2, 3 or 4 (Levanon et al, 1998; Brantjes et al, 2001; Daniels and Weis, 2005). Groucho/TLE proteins are co-repressors for a variety of DNA-binding transcription factors and mediate repression at least in part through their interaction with histone deacetylases such as RPD3/HDAC1 (Arce et al, 2009; Brantjes et al, 2001; Chen et al, 1999; reviewed in Chen and Courey, 2000). Groucho proteins have been shown to homo-tetramerize through a glutamine rich Q domain at the N-terminus, and this oligomerization is required for repression. The Q domain is also sufficient for interaction with TCF/LEF proteins (Brantjes et al, 2001; Chen et al, 1998; Pinto and Lobe, 1996; Song et al, 2004). Studies with purified proteins have shown that human TLE1 and 2 bind to an amino-terminal truncated form of LEF1(69-397) with an affinity comparable to that for full length LEF1 (Daniels and Weis, 2005)
Evidence suggests that upon activation of the WNT pathway, TLE proteins are displaced from TCF/LEF complexes by competition with nuclear beta-catenin. A primary N-terminal beta-catenin binding site has been defined on TCF/LEF. Beta-catenin binds this region of TCF/LEF through ARM domains 3-8; beta-catenin residues D19 and E27 are essential for this interaction (van de Wetering et al, 1997; Graham et al, 2000). The beta-catenin binding site on TCF/LEF does not overlap with the putative TLE binding site and is not required for TLE binding (Daniels and Weis, 2005; Poy et al, 2001; Graham et al, 2000; von Kries et al, 2000; Omer et al, 1999; Korinek et al, 1998; Behrens et al, 1996; Molenaar et al, 1996, van de Wetering et al, 1997). Limited proteolysis and competition studies with purified proteins suggests that TLEs and beta-catenin share a secondary C-terminal binding site on LEF-1; competition for this binding site is proposed to trigger the switch from repressive to activating complexes at the promoters of WNT target genes, though this may not be universally true at all WNT-responsive promoters (Daniels and Weis, 2005).