Bruton's Tyrosine Kinase Revealed As a Negative Regulator of Wnt-beta-catenin Signaling

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2009 May 28

PMID 19471023

Citations 30

Authors

Richard G James

Travis L Biechele

William H Conrad

Nathan D Camp

Daniel M Fass

Michael B Major

Karen Sommer

XianHua Yi

Brian S Roberts

Michele A Cleary

William T Arthur

Michael MacCoss

David J Rawlings

Stephen J Haggarty

Randall T Moon

Affiliations

Soon will be listed here.

Abstract

Wnts are secreted ligands that activate several receptor-mediated signal transduction cascades. Homeostatic Wnt signaling through beta-catenin is required in adults, because either elevation or attenuation of beta-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-beta-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-beta-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-beta-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 beta-catenin-mediated transcription in human colorectal cancer cells and B cells.

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