Volume 22, No 1, Jan 2012
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 22 Issue 1, January 2012: 237-247
ORIGINAL ARTICLES
Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation
Jungsug Gwak1,*, Sun Gwan Hwang2,3,*, Hyung-Soon Park4, Sang Rak Choi2, Sun-Hee Park5, Hyunjoon Kim6, Nam-Chul Ha5, Sung Jin Bae2, Jin-Kwan Han6, Dong-
1Department of Advanced Fermentation Fusion Science & Technology, Kookmin University, Seoul 136-702, Korea
2Drug Development Center, SK Biopharmaceuticals Co., Ltd, Daejeon 305-712, Korea
3Graduate School of Medicine, Laboratory of G Protein Coupled Receptor, Korea University, Seoul 135-705, Korea
4Probiond Co., Ltd., Seoul 143-834, Korea
5College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 609-735, Korea
6Division of Molecular and Life Sciences, POSTECH, Pohang 790-784, Korea
7Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Korea
Correspondence: Sangtaek Oh,(ohsa@kookmin.ac.kr)
The Wnt/β-catenin pathway plays important roles in the differentiation of multiple cell types, including mesenchymal stem cells. Using a cell-based chemical screening assay with a synthetic chemical library of 270 000 compounds, we identified the compound SKL2001 as a novel agonist of the Wnt/β-catenin pathway and uncovered its molecular mechanism of action. SKL2001 upregulated β-catenin responsive transcription by increasing the intracellular β-catenin protein level and inhibited the phosphorylation of β-catenin at residues Ser33/37/Thr41 and Ser45, which would mark it for proteasomal degradation, without affecting CK1 and GSK-3β; enzyme activities. Biochemical analysis revealed that SKL2001 disrupted the Axin/β;-catenin interaction, which is a critical step for CK1- and GSK-3β-mediated phosphorylation of β-catenin at Ser33/37/Thr41 and Ser45. The treatment of mesenchymal stem cells with SKL2001 promoted osteoblastogenesis and suppressed adipocyte differentiation, both of which were accompanied by the activation of Wnt/β-catenin pathway. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by modulation of the Wnt/β-catenin pathway.
Cell Research (2012) 22:237-247. doi:10.1038/cr.2011.127; published online 9 August 2011
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