Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction
- Authors
- Wang, S., Yin, J., Chen, D., Nie, F., Song, X., Fei, C., Miao, H., Jing, C., Ma, W., Wang, L., Xie, S., Li, C., Zeng, R., Pan, W., Hao, X., and Li, L.
- ID
- ZDB-PUB-130816-7
- Date
- 2013
- Source
- Nature Chemical Biology 9(9): 579-85 (Journal)
- Registered Authors
- Jing, Chang-Bin, Li, Lin, Pan, Weijun
- Keywords
- none
- MeSH Terms
-
- Animals
- Axin Protein/antagonists & inhibitors
- Axin Protein/chemistry
- Axin Protein/metabolism*
- Benzodioxoles/chemistry
- Benzodioxoles/pharmacology*
- HEK293 Cells
- Humans
- Low Density Lipoprotein Receptor-Related Protein-5/chemistry
- Low Density Lipoprotein Receptor-Related Protein-5/metabolism*
- Low Density Lipoprotein Receptor-Related Protein-6/chemistry
- Low Density Lipoprotein Receptor-Related Protein-6/metabolism*
- Phenanthridines/chemistry
- Phenanthridines/pharmacology*
- Protein Binding/drug effects
- Small Molecule Libraries/chemistry
- Small Molecule Libraries/pharmacology*
- Wnt Proteins/metabolism*
- Wnt Signaling Pathway/drug effects*
- Zebrafish/embryology
- Zebrafish/metabolism
- PubMed
- 23892894 Full text @ Nat. Chem. Biol.
The Wnt/β-catenin signaling pathway has a crucial role in embryonic development, stem cell maintenance and human disease. By screening a synthetic chemical library of lycorine derivatives, we identified 4-ethyl-5-methyl-5,6-dihydro-[1,3]dioxolo[4,5-j]phenanthridine (HLY78) as an activator of the Wnt/β-catenin signaling pathway, which acts in a Wnt ligand–dependent manner. HLY78 targets the DIX domain of Axin and potentiates the Axin–LRP6 association, thus promoting LRP6 phosphorylation and Wnt signaling transduction. Moreover, we identified the critical residues on Axin for HLY78 binding and showed that HLY78 may weaken the autoinhibition of Axin. In addition, HLY78 acts synergistically with Wnt in the embryonic development of zebrafish and increases the expression of the conserved hematopoietic stem cell (HSC) markers, runx1 and cmyb, in zebrafish embryos. Collectively, our study not only provides new insights into the regulation of the Wnt/β-catenin signaling pathway by a Wnt-specific small molecule but also will facilitate therapeutic applications, such as HSC expansion.