Small molecule-based disruption of the Axin/beta-catenin protein complex regulates mesenchymal stem cell differentiation
SCIE
SCOPUS
- Title
- Small molecule-based disruption of the Axin/beta-catenin protein complex regulates mesenchymal stem cell differentiation
- Authors
- Gwak, J; Hwang, SG; Park, HS; Choi, SR; Park, SH; Kim, H; Ha, NC; Bae, SJ; Han, JK; Kim, DE; Cho, JW; Oh, S
- Date Issued
- 2012-01
- Publisher
- INST BIOCHEMISTRY & CELL BIOLOGY
- Abstract
- The Wnt/beta-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/beta-catenin pathway and uncovered its molecular mechanism of action. SKL2001 upregulated beta-catenin responsive transcription by increasing the intracellular beta-catenin protein level and inhibited the phosphorylation of beta-catenin at residues Ser33/37/Thr41 and Ser45, which would mark it for proteasomal degradation, without affecting CK1 and GSK-3 beta enzyme activities. Biochemical analysis revealed that SKL2001 disrupted the Axin/beta-catenin interaction, which is a critical step for CK1- and GSK-3 beta-mediated phosphorylation of beta-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/beta-catenin pathway. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by modulation of the Wnt/beta-catenin pathway.
- Keywords
- Wnt pathway; Axin/beta-catenin complex; small molecule; mesenchymal stem cell; BETA-CATENIN; DESTRUCTION COMPLEX; CRYSTAL-STRUCTURE; BONE MASS; IN-VITRO; KAPPA-B; ADIPOGENESIS; OSTEOBLAST; PATHWAY; INHIBITORS
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/15978
- DOI
- 10.1038/CR.2011.127
- ISSN
- 1001-0602
- Article Type
- Article
- Citation
- CELL RESEARCH, vol. 22, no. 1, page. 237 - 247, 2012-01
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