PUBLICATION
Bruton's tyrosine kinase revealed as a negative regulator of Wnt-beta-catenin signaling
- Authors
- James, R.G., Biechele, T.L., Conrad, W.H., Camp, N.D., Fass, D.M., Major, M.B., Sommer, K., Yi, X., Roberts, B.S., Cleary, M.A., Arthur, W.T., MacCoss, M., Rawlings, D.J., Haggarty, S.J., and Moon, R.T.
- ID
- ZDB-PUB-090602-1
- Date
- 2009
- Source
- Science signaling 2(72): ra25 (Journal)
- Registered Authors
- Moon, Randall T.
- Keywords
- none
- MeSH Terms
-
- Chromatography, Affinity
- Cell Line
- Protein-Tyrosine Kinases/isolation & purification
- Protein-Tyrosine Kinases/metabolism*
- Animals
- PubMed
- 19471023 Full text @ Sci. Signal.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping