PT  - JOURNAL ARTICLE
AU  - James, Richard G.
AU  - Biechele, Travis L.
AU  - Conrad, William H.
AU  - Camp, Nathan D.
AU  - Fass, Daniel M.
AU  - Major, Michael B.
AU  - Sommer, Karen
AU  - Yi, XianHua
AU  - Roberts, Brian S.
AU  - Cleary, Michele A.
AU  - Arthur, William T.
AU  - MacCoss, Michael
AU  - Rawlings, David J.
AU  - Haggarty, Stephen J.
AU  - Moon, Randall T.
TI  - Bruton’s Tyrosine Kinase Revealed as a Negative Regulator of Wnt–β-Catenin Signaling
AID  - 10.1126/scisignal.2000230
DP  - 2009 May 26
TA  - Science Signaling
PG  - ra25--ra25
VI  - 2
IP  - 72
4099  - http://stke.sciencemag.org/content/2/72/ra25.short
4100  - http://stke.sciencemag.org/content/2/72/ra25.full
SO  - Sci. Signal.2009 May 26; 2
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.