Open AccessChemical biology reveals CARF as a positive regulator of canonical Wnt signaling by promoting TCF/β-catenin transcriptional activity
Author(s) -
Xiaoli He,
Wenjuan Zhang,
Chen Yan,
Fan Nie,
Chen Li,
Xiaofen Liu,
Fengyu Cong,
Shengdi Li,
Xiaomin Song,
Yingying Jia,
Rong Zeng,
Dianqing Wu,
Weijun Pan,
XiaoJiang Hao,
Lin Li
Publication year - 2017
Publication title -
cell discovery
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.412
H-Index - 29
ISSN - 2056-5968
DOI - 10.1038/celldisc.2017.3
Subject(s) - wnt signaling pathway , signal transduction , zebrafish , chemistry , microbiology and biotechnology , regulator , catenin , chemical biology , biology , biochemistry , gene
Wnt/β-catenin signaling regulates multiple biological processes and aberration of this pathway is frequently observed in human cancers. Previously, we uncovered NC043 as a small-molecule inhibitor of Wnt/β-catenin signaling. Here, we identified CARF as the cellular target of NC043. We found that NC043 binds directly to CARF through forming a covalent bond with the Cys-516 residue of CARF. Further study revealed that CARF interacts with Dvl, which potentiates the Dvl–c-Jun–β-catenin–TCF transcriptional complex and thus promotes Wnt signaling activation. NC043 could disrupt the interaction between CARF and Dvl, thereby impairing Wnt signal transduction. In line with this, knockdown of CARF in zebrafish leads to impairment of embryonic development, hematopoietic stem cell generation and caudal fin regeneration. Collectively, we identified CARF as the cellular target of NC043 and revealed CARF as a positive regulator of Wnt/β-catenin signal transduction.