Identification of Tcf4 residues involved in high-affinity β-catenin binding

The N-termini of members of the T-cell factor (Tcf) and lymphocyte-enhancement factor (Lef)protein families bind to beta-catenin, forming bipartite transcription factors which regulate expression of genes involved in organismal development and the growth of normal and malignant colon epithelium. Elevated levels of Tcf4:beta-catenin are found ire colon tumor cells with mutations in the adenomatous polyposis coli (APG) gene. The elevated-levels of Tcf4:beta-catenin result in increased-transcription of genes, including c-myc, important for the growth of these tumor cells. Here we analyze the interaction between beta-catenin and Tcf4 and:show that the N-terminal 53 amino acids of Tcf4 bind with high affinity to beta-catenin. We show that this high-affinity interaction involves multiple contact points including Tcf4 Asp-16, which is essential for beta-catenin binding. In addition to Tcf/Lef family members, beta-catenin binds to APC and cadherins. We found that the binding of beta-catenin to Tcf4, APC, or E-cadherin was mutually exclusive, These results are discussed with regard to how beta-catenin interacts with its binding partners and to the potential for identifying specific, small molecule inhibitors of these interactions. (C) 1999 Academic Press.