Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with beta-catenin.

Wnt signaling is thought to be mediated via interactions between β-catenin and members of the LEF-1/TCF family of transcription factors. Here we study the mechanism of transcriptional regulation by LEF-1 in response to a Wnt-1 signal under conditions of endogenous β-catenin in NIH 3T3 cells, and we examine whether association with β-catenin is obligatory for the function of LEF-1. We find that Wnt-1 signaling confers transcriptional activation potential upon LEF-1 by association with β-catenin in the nucleus. By mutagenesis, we identified specific residues in LEF-1 important for interaction with β-catenin, and we delineated two transcriptional activation domains in β-catenin whose function is augmented in specific association with LEF-1. Finally, we show that a Wnt-1 signal and β-catenin association are not required for the architectural function of LEF-1 in the regulation of the T-cell receptor α enhancer, which involves association of LEF-1 with a different cofactor, ALY. Thus, LEF-1 can assume diverse regulatory functions by association with different proteins.