Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells

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Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells
 
Fenderico, Nicola; van Scherpenzeel, Revina C.; Goldflam, Michael; Proverbio, Davide; Jordens, Ingrid; Kralj, Tomica; Stryeck, Sarah; Bass, Tarek Z.; Hermans, Guy; Ullman, Christopher; Aastrup, Teodor; Gros, Piet; Maurice, Madelon M.
(2019) Nature Communications, volume 10, issue 1, pp.
(Article)
Abstract
Wnt-induced β-catenin-mediated transcription is a driving force for stem cell self-renewal during adult tissue homeostasis. Enhanced Wnt receptor expression due to mutational inactivation of the ubiquitin ligases RNF43/ZNRF3 recently emerged as a leading cause for cancer development. Consequently, targeting canonical Wnt receptors such as LRP5/6 holds great promise for treatment ... read more
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Keywords: Animals, Binding Sites, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Crystallography, X-Ray, Fibroblasts/cytology, Gene Expression Regulation, HEK293 Cells, Humans, Intestine, Small/cytology, Low Density Lipoprotein Receptor-Related Protein-5/antagonists & inhibitors, Low Density Lipoprotein Receptor-Related Protein-6/antagonists & inhibitors, Mice, Models, Molecular, Organoids/cytology, Protein Binding, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Single-Domain Antibodies/chemistry, Stem Cells/cytology, Transcription, Genetic, Ubiquitin-Protein Ligases/genetics, Wnt3A Protein/genetics, beta Catenin/genetics, Journal Article, Research Support, Non-U.S. Gov't
DOI: https://doi.org/10.1038/s41467-018-08172-z
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We thank members of the laboratory of M.M.M. for experimental support, helpful discussions and suggestions. We thank the European Synchrotron Radiation Facility (ESRF) for the provision of synchrotron radiation facilities; and beamline scientists of the ESRF for assistance. We thank U-protein Express for the provision of protein expression facilities. We thank Guangyun Yu and Ronald Pieters (Utrecht University, Department of Pharmaceutical sciences - Molecular Pharmacy, The Netherlands), for providing access to the MicroCal Auto ITC200. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. This work was supported by European Research Council Starting Grant 242958, the Netherlands Organization for Scientific Research NWO VICI Grant 91815604, ECHO Grant 711.013.012 (to M.M.M.), European Union Grant FP7 Marie Curie ITN 608180 “WntsApp” (to M.M.M.), Fondazione Michelangelo for the Advancement of the Study and Treatment of Cancer (to N.F.), BioStruct-X Grant 283570 and NWO Spinoza Grant 01.80.104.00 (to P.G.). Publisher Copyright: © 2019, The Author(s).
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