title: Bruton's tyrosine kinase revealed as a negative regulator of Wnt-beta-catenin signaling.
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.
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Washington School of Medicine, Box 357370, Seattle, WA 98195, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: James
authors.forename: Travis L
authors.initials: TL
authors.lastname: Biechele
authors.forename: William H
authors.initials: WH
authors.lastname: Conrad
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Camp
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Fass
authors.forename: Michael B
authors.initials: MB
authors.lastname: Major
authors.forename: Karen
authors.initials: K
authors.lastname: Sommer
authors.forename: XianHua
authors.initials: X
authors.lastname: Yi
authors.forename: Brian S
authors.initials: BS
authors.lastname: Roberts
authors.forename: Michele A
authors.initials: MA
authors.lastname: Cleary
authors.forename: William T
authors.initials: WT
authors.lastname: Arthur
authors.forename: Michael
authors.initials: M
authors.lastname: MacCoss
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002460:Cell Line; D002846:Chromatography, Affinity; D006801:Humans; D013058:Mass Spectrometry; D011505:Protein-Tyrosine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human