Chemical Genetics Reveals a Role of dCTP Pyrophosphatase 1 in Wnt Signaling

Cell‐based screening is a powerful approach to identify novel chemical modulators and biological components of relevant biological processes. The canonical Wnt pathway is essential for normal embryonic development and tissue homeostasis, and its deregulation plays a crucial role in carcinogenesis. T...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2019-09, Vol.58 (37), p.13009-13013
Main Authors: Friese, Alexandra, Kapoor, Shobhna, Schneidewind, Tabea, Vidadala, Srinivasa Rao, Sardana, Juhi, Brause, Alexandra, Förster, Tim, Bischoff, Matthias, Wagner, Jessica, Janning, Petra, Ziegler, Slava, Waldmann, Herbert
Format: Article
Language:English
Subjects:
Biological activity
Carcinogenesis
Carcinogens
Deregulation
Embryogenesis
Embryonic growth stage
Embryos
Genetics
Homeostasis
Hydrolase
Inhibitors
Modulators
natural products
Organic chemistry
protein-protein interactions
Pyrophosphatase
Regulators
Signal monitoring
Signal transduction
Signaling
small-molecule inhibitors
target identification
Target recognition
Ubiquitin
Wnt pathway
Wnt protein
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Summary:Cell‐based screening is a powerful approach to identify novel chemical modulators and biological components of relevant biological processes. The canonical Wnt pathway is essential for normal embryonic development and tissue homeostasis, and its deregulation plays a crucial role in carcinogenesis. Therefore, the identification of new pathway members and regulators is of significant interest. By means of a cell‐based assay monitoring Wnt signaling we identified the pyrrolocoumarin Pyrcoumin as inhibitor of canonical Wnt signaling. Target identification and validation revealed that Pyrcoumin is a competitive inhibitor of dCTP pyrophosphatase 1 (dCTPP1). We demonstrate a yet unknown interaction of dCTPP1 with ubiquitin carboxyl‐terminal hydrolase (USP7) that is counteracted by dCTPP1 inhibitors. These findings indicate that dCTPP1 plays a role in regulation of Wnt/β‐catenin signaling most likely through a direct interaction with USP7. A cell‐based screening for inhibitors of canonical Wnt signaling identified the pyrrolocoumarin Pyrcoumin, a new competitive inhibitor of dCTP pyrophosphatase 1 (dCTPP1). Pyrcoumin counteracts the previously unknown interaction of dCTPP1 with ubiquitin carboxyl‐terminal hydrolase (USP7).
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201905977