Beta-catenin:TCF associates with BCL9 and PYGO

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Reaction [binding]
Homo sapiens
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Once tethered at WNT promoters, beta-catenin is a scaffold for the recruitment of a variety of transcriptional activators. The C-terminal end of beta-catenin interacts with a wide range of general transcriptional activators and chromatin remodelers, while the N-terminal region recruits more WNT-specific activators including BCL9 and Pygopus (reviewed in Jessen et al, 2008). BCL9 proteins (2 in vertebrates, BCL9 and BCL9L) interact with both beta-catenin and the putative activator Pygo (also 2 in vertebrates, Pygo1 and Pygo2) and in this way function as a bridging molecule to promote WNT-dependent transcription (reviewed in Valenta et al, 2012).
BCL9 was identified as the gene overexpressed in a B cell acute lymphoblastic leukemia cell line (Willis et al, 1998) and was subsequently found to be homologous to Legless (Lgs), a Drosophila gene identified in a number of screens for components of the WNT signalling pathway (Kramps et al, 2002; Belenkaya et al, 2002; Thompson et al, 2002). Lgs and BCL9 have no recognizable protein motifs and share sequence similarity only in three short stretches of 30 amino acids termed homology domains (HD) 1-3 (Kramps et al, 2002; reviewed in Valenta et al, 2012). HD1 mediates the interaction with the N-terminal ARM domain of beta-catenin while HD2 is required for the recruitment of Pygo through its C-terminal plant homology domain (PHD) (Kramps et al, 2002; Sampietro et al, 2006, Sierra et al, 2006). Replacement of the PHD domain of Pygo with the beta-catenin-interacting HD2 domain of Lgs rescues the phenotype of both lgs and pygo deletion in Drosophila suggesting that the primary role of Lgs is the recruitment of Pygo (Kramps et al, 2002). Transcriptional activation by Pygo depends on the conserved tripeptide NPF in the N-terminal homology domain (NHD) (Kramps et al, 2002; Hoffmans and Basler, 2004; Hoffmans et al, 2005; Städeli and Basler, 2005).
In Drosophila, Lgs is essential for Wg signalling, and deletion of either Lgs or Pygo phenocopies armadillo (the Drosophila beta-catenin homologue) null mutants (Kramps et al, 2002; Thompson et al, 2002). In mammals, the requirement and roles for BCL9 and Pygo are both less strict and less completely understood. Unlike in Drosophila, disruption of the BCL9/Pygo branch in mammals has less impact on transcriptional activation than abrogation of beta-catenin-dependent signalling through the C-terminal tail (Valenta et al, 2011). Ablation of pygopus genes in mice does not phenocopy with loss of Wnt signaling (Song et al, 2007; Schwab et al, 2007; Li et al, 2007), and disruption of the BCL9/BCL9L beta-catenin interaction results in embryonic lethality three days later than in the case of complete disruption of beta-catenin-dependent transcription (Valenta et al, 2011). Mammalian BCL9 also has Pygo-independent roles in WNT signaling and has been shown to interact directly with other transcriptional co-activators such as CBP/p300 or TRRAP/GCN5 through its C-terminus (Sustmann et al, 2008). Finally, the PHD of Pygo is able to bind methylated histones, which may contribute to context-specific roles of the protein (Gu et al, 2009; Fielder et al, 2008; Kessler et al, 2009; Gu et al, 2012).

Literature References
PubMed ID Title Journal Year
22617422 The many faces and functions of ?-catenin

Valenta, T, Hausmann, G, Basler, K

EMBO J. 2012
17458864 Developmental phenotypes and reduced Wnt signaling in mice deficient for pygopus 2

Munguia, JE, Li, B, Jessen, S, Dai, X, Waterman, ML, Piccolo, S, Hu, M, Rhéaume, C, Bilanchone, V, Teng, A

Genesis 2007
17428831 pygopus 2 has a crucial, Wnt pathway-independent function in lens induction

Lin, X, Song, N, Yamaguchi, T, Lang, RA, Patterson, LT, Potter, SS, Schwab, KR

Development 2007
17425782 Pygo1 and Pygo2 roles in Wnt signaling in mammalian kidney development

Lin, X, Song, N, Lang, RA, Patterson, LT, Potter, SS, Hartman, HA, Schwab, KR

BMC Biol. 2007
18498752 Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex

Müller, J, Sánchez-Barrena, MJ, Bienz, M, Mieszczanek, J, Rybin, V, Fiedler, M, Nekrasov, M, Evans, P

Mol. Cell 2008
11988739 A new nuclear component of the Wnt signalling pathway

Thompson, B, Rosin-Arbesfeld, R, Musisi, H, Bienz, M, Townsley, F

Nat. Cell Biol. 2002
16005293 Pygopus and legless provide essential transcriptional coactivator functions to armadillo/beta-catenin

Hoffmans, R, Basler, K, Städeli, R

Curr. Biol. 2005
11955446 Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex

Murone, M, Froesch, B, Basler, K, Nellen, D, Kramps, T, Zullig, S, Brunner, E, Chatterjee, S, Peter, O

Cell 2002
22190459 Probing transcription-specific outputs of ?-catenin in vivo

Aguet, M, Steiner, S, Hoffmans, R, Draganova, K, Valenta, T, Sommer, L, Zemke, M, Basler, K, Cinelli, P, Gay, M

Genes Dev. 2011
22186018 Pygo2 regulates histone gene expression and H3 K56 acetylation in human mammary epithelial cells

Dai, X, Watanabe, K, Gu, B

Cell Cycle 2012
12163411 pygopus Encodes a nuclear protein essential for wingless/Wnt signaling

Lin, X, Han, C, Houston, DW, Heasman, J, Lin, X, Belenkaya, TY, Standley, HJ

Development 2002
18404694 Pygopus and the Wnt signaling pathway: a diverse set of connections

Jessen, S, Dai, X, Gu, B

Bioessays 2008
19493659 The PHD domain is required to link Drosophila Pygopus to Legless/beta-catenin and not to histone H3

Kessler, R, Hausmann, G, Basler, K

Mech. Dev. 2009
17052462 Crystal structure of a beta-catenin/BCL9/Tcf4 complex

Xu, W, Hinds, TR, Cho, US, Sampietro, J, Dahlberg, CL, Kimelman, D

Mol. Cell 2006
16169192 Dissecting nuclear Wingless signalling: recruitment of the transcriptional co-activator Pygopus by a chain of adaptor proteins

Stadeli, R, Basler, K

Mech Dev 2005
16510874 The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes

Yoshida, T, Jones, KA, Sierra, J, Joazeiro, CA

Genes Dev. 2006
18347063 Cell-type-specific function of BCL9 involves a transcriptional activation domain that synergizes with beta-catenin

Flach, H, Eastman, Q, Ebert, H, Sustmann, C, Grosschedl, R

Mol. Cell. Biol. 2008
15294866 Identification and in vivo role of the Armadillo-Legless interaction

Hoffmans, R, Basler, K

Development 2004
9490669 Molecular cloning of translocation t(1;14)(q21;q32) defines a novel gene (BCL9) at chromosome 1q21

Willis, TG, Stul, M, Jadayel, DM, Catovsky, D, Coignet, LJ, Treleaven, JG, Dyer, MJ, Silva, ML, Bastard, C, Zalcberg, IR, Wlodarska, I

Blood 1998
19487454 Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation

Agrawal, A, Li, B, Li, A, Dai, X, Millar, S, Gu, B, Lewis, MT, Veltmaat, JM, Moraes, RC, Lee, EY, Rhéaume, C, Bilanchone, V, Takemaru, K, Sun, P, Teng, A, Yuan, Y

J. Cell Biol. 2009
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