Beta-catenin displaces TLE:HDAC1 from TCF/LEF

Stable Identifier
Reaction [dissociation]
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
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Kral, AM, Omer, CA, Miller, PJ, Diehl, RE

Biochem Biophys Res Commun 1999
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Bejsovec, A, van De Wetering, M, Peifer, M, Loureiro, J, Clevers, HC, van Beest, M, Cavallo, R, Hursh, D, Mortin, M, Jones, T, van Es, J, Ypma, A, Dooijes, D

Cell 1997
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Chen, G, Mische, S, Fernandez, J, Courey, AJ

Genes Dev. 1999
9819412 A role for Groucho tetramerization in transcriptional repression

Chen, G, Courey, AJ, Nguyen, PH

Mol. Cell. Biol. 1998
11136974 Crystal structure of a beta-catenin/Tcf complex

Xu, W, Mao, F, Graham, TA, Weaver, C, Kimelman, D

Cell 2000
15768032 Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation

Weis, WI, Daniels, DL

Nat Struct Mol Biol 2005
15121853 Groucho oligomerization is required for repression in vivo

Hasson, P, Paroush, Z, Song, H, Courey, AJ

Mol. Cell. Biol. 2004
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Grosschedl, R, Wedlich, D, Bruhn, L, Kühl, M, Birchmeier, W, von Kries, JP, Behrens, J

Nature 1996
19460168 Groucho binds two conserved regions of LEF-1 for HDAC-dependent repression

Arce, L, Waterman, ML, Pate, KT

BMC Cancer 2009
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Chen, G, Courey, AJ

Gene 2000
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Pinto, M, Lobe, CG

J. Biol. Chem. 1996
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Barker, N, Clevers, HC, Brantjes, H, van Es, J

Biol. Chem. 2002
9488439 Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse

Barker, N, Clevers, HC, Markman, M, Destrée, O, Korinek, V, Lamers, W, Wagenaar, G, Willert, K, Roose, J, Molenaar, M

Mol. Cell. Biol. 1998
8756721 XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos

van De Wetering, M, Clevers, HC, Destrée, O, Peterson-Maduro, J, Korinek, V, Oosterwegel, M, Roose, J, Godsave, S, Molenaar, M

Cell 1996
9751710 Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors

Paroush, Z, Goldstein, RE, Groner, Y, Tang, H, Bernstein, Y, Levanon, D, Goldenberg, D, Stifani, S

Proc. Natl. Acad. Sci. U.S.A. 1998
11713476 Structure of a human Tcf4-beta-catenin complex

Lepourcelet, M, Shivdasani, RA, Eck, MJ, Poy, F

Nat Struct Biol 2001
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