Parafibromin/Hyrax Activates Wnt/Wg Target Gene Transcription by Direct Association with β-catenin/Armadillo

• Published in: Cell 2006-04, Vol.125 (2), p.327-341
• Main Authors: Mosimann, Christian, Hausmann, George, Basler, Konrad
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Animals; Axin Protein; beta Catenin - genetics; beta Catenin - metabolism; Cell Line; Drosophila; Drosophila melanogaster - anatomy & histology; Drosophila melanogaster - physiology; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Molecular Sequence Data; Phylogeny; Sequence Alignment; Signal Transduction - physiology; Transcription, Genetic; Tumor Suppressor Proteins - classification; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Two-Hybrid System Techniques; Wings, Animal - anatomy & histology; Wings, Animal - growth & development; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2006.01.053

The Wnt pathway controls cell fates, tissue homeostasis, and cancer. Its activation entails the association of β-catenin with nuclear TCF/LEF proteins and results in transcriptional activation of target genes. The mechanism by which nuclear β-catenin controls transcription is largely unknown. Here we genetically identify a novel Wnt/Wg pathway component that mediates the transcriptional outputs of β-catenin/Armadillo. We show that Drosophila Hyrax and its human ortholog, Parafibromin, components of the Polymerase-Associated Factor 1 (PAF1) complex, are required for nuclear transduction of the Wnt/Wg signal and bind directly to the C-terminal region of β-catenin/Armadillo. Moreover, we find that the transactivation potential of Parafibromin/Hyrax depends on the recruitment of Pygopus to β-catenin/Armadillo. Our results assign to the tumor suppressor Parafibromin an unexpected role in Wnt signaling and provide a molecular mechanism for Wnt target gene control, in which the nuclear Wnt signaling complex directly engages the PAF1 complex, thereby controlling transcriptional initiation and elongation by RNA Polymerase II.