8z61
From Proteopedia
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/CTNB1_HUMAN CTNB1_HUMAN] Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.<ref>PMID:17524503</ref> <ref>PMID:18086858</ref> <ref>PMID:18957423</ref> <ref>PMID:21262353</ref> | [https://www.uniprot.org/uniprot/CTNB1_HUMAN CTNB1_HUMAN] Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.<ref>PMID:17524503</ref> <ref>PMID:18086858</ref> <ref>PMID:18957423</ref> <ref>PMID:21262353</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Aberrant activation of the Wnt/beta-catenin signaling is associated with tumor development, and blocking beta-catenin/BCL9 is a novel strategy for oncogenic Wnt/beta-catenin signaling. Herein, we presented two novel beta-catenin variations and exposed conformational dynamics in several beta-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting beta-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of beta-catenin. Among them, 28 had a strong affinity for beta-catenin (K(d) = 82 nM), the most potent inhibitor reported. In addition, 13 and 35 not only activate T cells but also promote the antigen presentation of cDC1, showing robust antitumor efficacy in the CT26 model. Collectively, our study demonstrated a series of potent small-molecule inhibitors targeting beta-catenin/BCL9, which can enhance antigen presentation and activate cDC1 cells, delivering a potential strategy for boosting innate and adaptive immunity to overcome immunotherapy resistance. | ||
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| + | Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting beta-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells.,Zhu W, Liu C, Xi K, Li A, Shen LA, Li Y, Jia M, He Y, Chen G, Liu C, Chen Y, Chen K, Sun F, Zhang D, Duan C, Wang H, Wang D, Zhao Y, Meng X, Zhu D J Med Chem. 2024 Jun 24. doi: 10.1021/acs.jmedchem.3c02079. PMID:38912577<ref>PMID:38912577</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 8z61" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Human beta-catenin crystal structure
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