Once in the nucleus, beta-catenin is recruited to WNT target genes through interaction with TCF/LEF transcription factors. This family, which consists of TCF7 (also known as TCF1), TCF7L1 (also known as TCF3), TCF7L2 (also known as TCF4) and TCF7L3 (also known as LEF1), are HMG-containing transcription factors that bind to the WNT responsive elements in target gene promoters (reviewed in Brantjes et al, 2002). In the absence of WNT signal, TCF/LEF proteins recruit Groucho/TLE repressors to inhibit transcription; upon WNT stimulation, beta-catenin can displace Groucho/TLE from TCF/LEF proteins to initiate transcriptional activation (reviewed in Chen and Courey, 2000). Although this model for WNT-dependent activation of target genes is widely accepted, it is important to note that TCF/LEF proteins are not redundant and can contribute to WNT target gene expression in a number of different ways (reviewed in Brantjes et al, 2002; MacDonald et al, 2009). In particular, TCF7L1 (TCF3) is thought to have a more pronounced repressor function than other TCF/LEF family members. A couple of recent studies in Xenopus and mammalian cells show that WNT- and beta-catenin-dependent phosphorylation of TCF7L1(TCF3) promotes its dissociation from the promoter of target genes and allows gene expression through relief of this repression activity (Hikasa et al, 2010; Hikasa et al, 2011).
The role of beta-catenin at WNT promoters hinges upon its ability to act as a scaffold for the recruitment of other proteins. The structure of beta-catenin consists of 12 imperfect ARM repeats (R1-12) flanked by an N-terminal and C-terminal extension (NTD and CTD respectively), with a conserved Helix C located between R12 and the CTD. Nuclear beta-catenin interacts with TCF/LEF at WNT target genes through ARM domains 3-9 (Graham et al, 2000; Poy et al, 2001; Xing et al, 2008). The N and the C terminal regions are important for the recruitment of transcriptional activator and repressors that contribute to WNT target gene expression (reviewed in Mosimann et al, 2009; Valenta et al, 2012). The N-terminal ARM domains 1-4 recruit the WNT-pathway specific activators BCL9:PYGO while the C-terminal region (R11-CTD) interacts with a wide range of general transcriptional activators that are involved in chromatin remodelling and transcription initiation. These include HATs such as P300, CBP and TIP60, histone methyltransferases such as MLL1 and 2, SWI/SNF factors BRG1 and ISWI and components of the PAF complex (reviewed in Mosimann et al, 2009; Valenta et al, 2012). Although many binding partners have been identified for the C-terminal region of beta-catenin, in many cases the timing and relationship of these interactions and indeed, the exact complex composition remains to be elucidated. Moreover, because many of the interacting partners appear to bind to overlapping regions of beta-catenin, it is unlikely that they all bind simultaneously. For simplicity, the interactions have been depicted as though they occur independently of one another; more accurately they are likely to cycle successively on and off beta-catenin to promote an active chromatin structure (reviewed in Willert and Jones, 2006; Valenta et al, 2012).