| Autor: |
James RG; Department of Pharmacology, Howard Hughes Medical Institute, University of Washington School of Medicine, Box 357370, Seattle, WA 98195, USA., Biechele TL, Conrad WH, Camp ND, Fass DM, Major MB, Sommer K, Yi X, Roberts BS, Cleary MA, Arthur WT, MacCoss M, Rawlings DJ, Haggarty SJ, Moon RT |
| Jazyk: |
angličtina |
| Zdroj: |
Science signaling [Sci Signal] 2009 May 26; Vol. 2 (72), pp. ra25. Date of Electronic Publication: 2009 May 26. |
| DOI: |
10.1126/scisignal.2000230 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
