Bruton's tyrosine kinase revealed as a negative regulator of wnt-b-catenin signaling

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

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)ra25
JournalScience signaling
Volume2
Issue number72
DOIs
StatePublished - May 26 2009

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