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.