Pygopus and legless provide essential transcriptional coactivator functions to armadillo/beta-catenin.

Wnt signaling controls important aspects of animal development, and its deregulation has been causally linked to cancer. Transduction of Wnt signals entails the association of beta-catenin with nuclear TCF DNA binding proteins and the subsequent activation of target genes. The transcriptional activity of Armadillo (Arm, the Drosophila beta-catenin homolog) largely depends on two recently discovered components, Legless (Lgs) and Pygopus (Pygo). Lgs functions as an adaptor between Arm/beta-catenin and Pygo, but different mechanisms have been proposed as to how Arm/beta-catenin is controlled by Lgs and Pygo. Although Lgs and Pygo were originally thought to serve as nuclear cofactors for Arm/beta-catenin to enhance its transactivation capacity, a recent analysis argued that they function instead to target Arm/beta-catenin to the nucleus. Here, we used genetic assays in cultured cells and in vivo to discriminate between the two paradigms. Regardless of the measures taken to maintain the nuclear presence of Arm/beta-catenin, a transcriptional-activation function of Pygo could not be bypassed. Our findings therefore indicate that Arm/beta-catenin depends on Lgs and Pygo primarily for its transcriptional output rather than for its nuclear import.