RT Journal Article SR Electronic T1 Bruton’s Tyrosine Kinase Revealed as a Negative Regulator of Wnt–β-Catenin Signaling JF Science Signaling JO Sci. Signal. FD American Association for the Advancement of Science SP ra25 OP ra25 DO 10.1126/scisignal.2000230 VO 2 IS 72 A1 James, Richard G. A1 Biechele, Travis L. A1 Conrad, William H. A1 Camp, Nathan D. A1 Fass, Daniel M. A1 Major, Michael B. A1 Sommer, Karen A1 Yi, XianHua A1 Roberts, Brian S. A1 Cleary, Michele A. A1 Arthur, William T. A1 MacCoss, Michael A1 Rawlings, David J. A1 Haggarty, Stephen J. A1 Moon, Randall T. YR 2009 UL http://stke.sciencemag.org/content/2/72/ra25.abstract AB Wnts are secreted ligands that activate several receptor-mediated signal transduction cascades. Homeostatic Wnt signaling through β-catenin is required in adults, because either elevation or attenuation of β-catenin function has been linked to diverse diseases. To contribute to the identification of both protein and pharmacological regulators of this pathway, we describe a combinatorial screen that merged data from a high-throughput screen of known bioactive compounds with an independent focused small interfering RNA screen. Each screen independently revealed Bruton’s tyrosine kinase (BTK) as an inhibitor of Wnt–β-catenin signaling. Loss of BTK function in human colorectal cancer cells, human B cells, zebrafish embryos, and cells derived from X-linked agammaglobulinemia patients with a mutant BTK gene resulted in elevated Wnt–β-catenin signaling, confirming that BTK acts as a negative regulator of this pathway. From affinity purification–mass spectrometry and biochemical binding studies, we found that BTK directly interacts with a nuclear component of Wnt–β-catenin signaling, CDC73. Further, we show that BTK increased the abundance of CDC73 in the absence of stimulation and that CDC73 acted as a repressor of β-catenin–mediated transcription in human colorectal cancer cells and B cells.