Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press TCF/LEFs and Wnt Signaling in the Nucleus Ken M. Cadigan1 and Marian L. Waterman2 1Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1048 2Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California 92697-4025 Correspondence: [email protected] T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors are the major end point mediators of Wnt/Wingless signaling throughout metazoans. TCF/LEFs are multifunc- tional proteins that use their sequence-specific DNA-binding and context-dependent inter- actions to specify which genes will be regulated by Wnts. Much of the work to define their actions has focused on their ability to repress target gene expression when Wnt signals are absent and to recruit b-catenin to target genes for activation when Wnts are present. Recent advances have highlighted how these on/off actions are regulated by Wnt signals and sta- bilized b-catenin. In contrast to invertebrates, which typically contain one TCF/LEF protein that can both activate and repress Wnt targets, gene duplication and isoform complexity of the family in vertebrates have led to specialization, in which individual TCF/LEF isoforms have distinct activities. nt signals play important roles during ligands, ten receptors, alternative receptors, its Wanimal development (Logan and Nusse signal transduction components, as well as the 2004), as well as in adult tissues that are re- cell’s particular developmental history. Despite freshed and repaired by stem cells (Haegebarth this complexity, many Wnt signals act through and Clevers 2009). It is the essential function of a single mediator, b-catenin, to regulate gene Wnt signaling in stem cell self-renewal and cell expression. Wnt ligand–receptor interactions proliferation that links this pathway to problems at the plasma membrane are communicated to of aging and disease such as cancer and diabetes target genes by the translocation of b-catenin (Polakis 2007; Laudes 2011). The term “Wnt into the nucleus where it partners with DNA- signaling” does not imply a single-purpose sig- binding proteins that recognize specific se- nal transduction system. Rather, it refers to a quence motifs in promoters and enhancers of diverse collection of signals triggered by Wnt target genes. The central 12-armadillo repeat ar- ligand–receptor interactions that direct cell ray of b-catenin is the main mediator of tran- behavior in multiple ways: cell polarity, move- scription factor interactions, whereas domains ment, proliferation, differentiation, survival and in the amino and carboxy termini carry potent self-renewal. Diversity in Wnt signaling derives transcription-activating functions (Orsulic and from the diversity of its components, its set of 19 Peifer 1996; van de Wetering et al. 1997; Hsu Editors: Roel Nusse, Xi He, and Renee van Amerongen Additional Perspectives on Wnt Signaling available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a007906 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a007906 1 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press K.M. Cadigan and M.L. Waterman et al. 1998). Thus, once b-catenin is recruited to (HMG DBD) (Fig. 1). The HMG DBD can rec- target genes, transcription is activated via the ognize specific DNA sequences with nanomolar actions of these domains and an array of tran- affinity (Giese et al. 1991; van de Wetering and scriptional coactivators (Mosimann et al. 2009; Clevers 1992; Love et al. 1995). In addition to Cadigan 2012). DNA sequence specificity, the HMG box has a Multiple transcription factors that recruit DNA bending function. It recognizes its specific b-catenin to Wnt targets have been identified nucleotide sequence in the minor groove of the and this review will summarize those that are DNA and enforces a bend in the helix between best characterized. However, the nuclear medi- 908 and 1278 (Giese et al. 1995; Love et al. 1995). ators most closely associated with Wnt/b-cat- Both directed and random screen studies have enin action are the TCF/LEFs, high-mobility identified a consensus recognition sequence for group (HMG) DNA-binding proteins with mul- the HMG DBD; 50-SCTTTGATS-30 (Fig. 2) (van tiple domains for protein interaction and regu- de Wetering et al. 1997; van Beest et al. 2000; lation. This review will focus attention on this Hallikas and Taipale 2006; Atcha et al. 2007). family of factors and discuss recent advances Recent chromatin immunoprecipitation experi- that shed light on how Wnt signaling works in ments to define TCF/LEF-b-catenin-binding stem cell niches and differentiation. patterns genome wide identify this consensus as the most frequently occurring sequence in TCF4 and b-catenin-binding peaks (Hatzis TCF/LEF TRANSCRIPTION FACTOR FAMILY et al. 2008; Blahnik et al. 2010; Bottomly et al. Almost all invertebrate genomes carry a single 2010; Norton et al. 2011). The small basic tail TCF/LEF ortholog, whereas vertebrates have motif is located nine residues carboxy terminal expanded to a family of four members (five in to the HMG box and serves two purposes: ele- the Zebrafish) (Fig. 1) (Arce et al. 2006; Arch- vating DNA-binding affinity through contact bold et al. 2012). The first discoveries of TCF/ with the positively charged DNA backbone and LEFs came from searches for transcription reg- functioning as a strong nuclear localization sig- ulators of cell-fate markers in human T lym- nal for interactions with importins (Giese et al. phocytes. “T cell factor 1” (HUGO gene name 1991; Prieve et al. 1998). TCF7 [van de Wetering et al. 1991]) and “lym- phoid enhancer factor 1” (HUGO gene name b-Catenin-Binding Domain LEF1 [Travis et al. 1991; Waterman et al. 1991]) were discovered in T and B cells. T cell factor The connection between TCF/LEFs and Wnt 3 and T cell factor 4 were found later through signaling came from yeast two-hybrid screens low-stringency hybridization screens with TCF7 suggesting that b-catenin could bind tightly cDNAs (HUGO gene names, TCF7L1, TCF7L2 to LEF1 and TCF1, an interaction subsequently [Korinek et al. 1998b]). The immunology-con- delimited to a conserved motif in the amino nected nomenclature is thus historical, and as terminus of TCF/LEFs (Fig. 1) (Behrens et al. knockout studies and expression studies attest, 1996; Huber et al. 1996; Molenaar et al. 1996; these factors play important regulatory roles in van de Wetering et al. 1997; Graham et al. 2000; almost all tissues of the body (Oosterwegel et al. Poy et al. 2001). Deletion of this domain was 1993; Brunner et al. 1997; van de Wetering et al. an important step in establishing TCF/LEFs 1997; Lin et al. 1998; Archbold et al. 2012). as downstream mediators of Wnt and b-cate- nin. Truncated “dominant negatives” could no longer bind to b-catenin, they suppressed the DNA-Binding Domain ability of overexpressed Wnt or b-catenin to in- All TCF/LEFs contain a highly conserved HMG duce secondary axes in frog embryos, and they box and a small peptide motif of basic residues phenocopied the segment polarity defect wing- (“basic tail”); together the HMG box and basic less mutants in Drosophila (Behrens et al. 1996; tail comprise the HMG DNA-binding domain Huber et al. 1996; Molenaar et al. 1996; van de 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a007906 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Wnt Target Gene Regulation A β-catenin-binding domain Basic tail TCF 100 aa HMG domain GBS C clamp B β-Catenin-binding domain ** * A. queenslandica ---gaavvssng-----------------dpelats—devkeychegegektehlnsm--------d----lhdiktelekdaeesetpttssnnn H. magnipapillata mpqlptsta--------------------e-eygae—deiklytqe-----edecsdt--------stvdvvndikddllnedgpd-----trkpn S. mansoni m------------------------------evact—devkvykdegeedeqkk----ssenlte-dkvglvi-----egegqgqd-----vpnqf C. elegans m----------------------------a-deelg—devkvfrrdedadddpmisgetseqqla-ddkkeav-----meaeldga-----grnps D. melanogaster mphthsrhgssg-----------------d-dlcst—devkifkdegdredeki----ssenllv-eeksslidl-----teseek-----ghkis S. purpuratus mpqqhsrgg--------------------e-ddgpp—detktyhteg-eqeekasenvvgp-r---dsfdhlndvkssl---idegesvsqkgsss H. sapiens-TCF1E mpqldsggggaggg---------------d-dlgap—dellafqdeg-eeqddksrdsaagper--d----laelkssl---vnesegaaggagip H. sapiens-TCF4E mpqlnggggd---------------------dlgan—delisfkdeg—eqeekssen-ssaer---d----ladvkssl---vnesetnqnsssds H. sapiens-LEF1 mpqlsgggggggg----------------dpelcat—demipfkdegdpqkekifaei-shpeeegd----ladikssl---vneseii-pasngh H. sapiens-TCF3 mpqlggggggggggsgggggssagaagggd-dlgan—delipfqdeggeeqepssdsa-sa---qrd----ldevkssl---vnesenq-ssssds HMG domain Basic tail A. queenslandica kkphikkplnafmlfmkekraevikec--tlkesaainqilgkmwhkldkseqakyyemareerarhmqmypgwsardnya-ahkkrrkkrsk H. magnipapillata krphvkkplnafmlymkeqrpkiaaef--tlkesaainqilgkrwhalekteqakyyemarkeraihmqlypgwsardnyaqigrkkkrprdk S. mansoni krvhikkplnafmlfmkdmrpivqeec--tlkesaainqilgkkwhelsrdkqakyyelarkekelhhqlfpgwsardnyaihsrrkkkrkla C. elegans kddhvkkplnafmwfmkenrkalleeignnekqsaelnkelgkrwhdlskeeqakyfemakkdkethkerypewsarenyavnkkktkkrrdk D. melanogaster kkphikkplnafmlymkemrakvvaec--tlkesaainqilgrrwhelsreeqskyyekarqerqlhmelypgwsardnygyvskkkkrkkdr S. purpuratus