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
-
- Animals
- Cell Line
- Chromatography, Affinity
- Humans
- Mass Spectrometry
- Protein-Tyrosine Kinases/isolation & purification
- Protein-Tyrosine Kinases/metabolism*
- Signal Transduction*
- Wnt Proteins/metabolism*
- beta Catenin/metabolism*
- PubMed
- 19471023 Full text @ Sci. Signal.
Citation
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. (2009) Bruton's tyrosine kinase revealed as a negative regulator of Wnt-beta-catenin signaling. Science signaling. 2(72):ra25.
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