|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Rosenbluh, J, Nijhawan, D, Cox, AG, Li, X, Schafer, EJ, Zack, TI, Wang, X, Tsherniak, A, Schinzel, AC, Shao, DD, Schumacher, SE, Weir, BA, Vazquez, F, Cowley, GS, Root, DE, Mesirov, JP, Beroukhim, R, Hahn, WC|
Wnt/β-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of β-catenin in transformation, we classified β-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that β-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with β-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of β-catenin-dependent cancers in both cell lines and animal models. These observations define a β-catenin-YAP1-TBX5 complex essential to the transformation and survival of β-catenin-driven cancers.