title: Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction.
abstract: 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.
authors.affiliation: 1] State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. [2].
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.forename: Junlin
authors.initials: J
authors.lastname: Yin
authors.forename: Duozhi
authors.initials: D
authors.lastname: Chen
authors.forename: Fen
authors.initials: F
authors.lastname: Nie
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Song
authors.forename: Cong
authors.initials: C
authors.lastname: Fei
authors.forename: Haofei
authors.initials: H
authors.lastname: Miao
authors.forename: Changbin
authors.initials: C
authors.lastname: Jing
authors.forename: Wenjing
authors.initials: W
authors.lastname: Ma
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Sichun
authors.initials: S
authors.lastname: Xie
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.forename: Weijun
authors.initials: W
authors.lastname: Pan
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Hao
authors.forename: Lin
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000737:chemistry / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry / Q000378:metabolism*; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
chemical_list: C584141:4-ethyl-5-methyl-5,6-dihydro(1,3)dioxolo(4,5-j)phenanthridine; D060466:Axin Protein; D052117:Benzodioxoles; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010617:Phenanthridines; D054852:Small Molecule Libraries; D051153:Wnt Proteins
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