Reactome | Beta-catenin displaces TLE:HDAC1 from TCF/LEF

Beta-catenin displaces TLE:HDAC1 from TCF/LEF

Stable Identifier

R-HSA-3299569

Type

Reaction

Species

Homo sapiens

Compartment

nucleoplasm

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Beta-catenin displaces TLE:HDAC1 from TCF/LEF

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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
11713476	Structure of a human Tcf4-beta-catenin complex Lepourcelet, M, Shivdasani, RA, Eck, MJ, Poy, F	Nat Struct Biol	2001
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
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
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
11934263	TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling Barker, N, Clevers, HC, Brantjes, H, van Es, J	Biol. Chem.	2002
8955148	Products of the grg (Groucho-related gene) family can dimerize through the amino-terminal Q domain Pinto, M, Lobe, CG	J. Biol. Chem.	1996
10831834	Groucho/TLE family proteins and transcriptional repression Chen, G, Courey, AJ	Gene	2000
19460168	Groucho binds two conserved regions of LEF-1 for HDAC-dependent repression Arce, L, Waterman, ML, Pate, KT	BMC Cancer	2009
8757136	Functional interaction of beta-catenin with the transcription factor LEF-1 Grosschedl, R, Wedlich, D, Bruhn, L, Kühl, M, Birchmeier, W, von Kries, JP, Behrens, J	Nature	1996
15121853	Groucho oligomerization is required for repression in vivo Hasson, P, Paroush, Z, Song, H, Courey, AJ	Mol. Cell. Biol.	2004
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
11136974	Crystal structure of a beta-catenin/Tcf complex Xu, W, Mao, F, Graham, TA, Weaver, C, Kimelman, D	Cell	2000
9819412	A role for Groucho tetramerization in transcriptional repression Chen, G, Courey, AJ, Nguyen, PH	Mol. Cell. Biol.	1998
10485845	A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development Chen, G, Mische, S, Fernandez, J, Courey, AJ	Genes Dev.	1999
9118222	Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF 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
10080941	Identification of Tcf4 residues involved in high-affinity beta-catenin binding Kral, AM, Omer, CA, Miller, PJ, Diehl, RE	Biochem Biophys Res Commun	1999