Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling
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dc.contributor.author | Janda, Claudia Y. | |
dc.contributor.author | Dang, Luke T. | |
dc.contributor.author | You, Changjiang | |
dc.contributor.author | Chang, Junlei | |
dc.contributor.author | de Lau, Wim | |
dc.contributor.author | Zhong, Zhendong A. | |
dc.contributor.author | Yan, Kelley S. | |
dc.contributor.author | Marecic, Owen | |
dc.contributor.author | Siepe, Dirk | |
dc.contributor.author | Li, Xingnan | |
dc.contributor.author | Moody, James D. | |
dc.contributor.author | Williams, Bart O. | |
dc.contributor.author | Clevers, Hans | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Baker, David | |
dc.contributor.author | Kuo, Calvin J. | |
dc.contributor.author | Garcia, K. Christopher | |
dc.date.accessioned | 2021-12-23T16:23:34Z | - |
dc.date.available | 2021-12-23T16:23:34Z | - |
dc.date.issued | 2017 | |
dc.identifier.issn | 00280836 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14583 | - |
dc.description.abstract | Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing beta-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues(1). The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors(2-4). As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic beta-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine. | |
dc.description.sponsorship | National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 GM097015, K08DK096048, U01 DK085527, U19 AI116484, U01 CA176299]; DFGGerman Research Foundation (DFG)European Commission [SFB 944]; Bu,rroughs Wellcome Fund CAMSBurroughs Wellcome Fund; Stinehart/Reed Foundation; Ludwig Foundation; Howard Hughes Medical InstituteHoward Hughes Medical Institute; European UnionEuropean Commission [668294]; NWO translational Adult Stem Cell Research grant [40-41400-98-1108]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA217851, U01CA176299] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [U19AI116484] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [K08DK096048, U01DK085527] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM097015, T32GM007266] Funding Source: NIH RePORTER; We thank the staff of the Advanced Light Source (ALS), Lawrence Berkeley National Laboratory, for support and access to beamline 8.2.2, and P. Chu from the Department of Comparative Medicine Animal Histology Service Center for sample preparation. This work was supported by National Institutes of Health (NIH) R01 GM097015 (to K.C.G), K08DK096048 (to K.S.Y), U01 DK085527 (to C.J.K.), U19 AI116484 (to C.J.K.), U01 CA176299 (to C.J.K.); DFG SFB 944 (to J.P.); Bu,rroughs Wellcome Fund CAMS (to K.S.Y.); the Stinehart/Reed Foundation (to K.C.G.); the Ludwig Foundation (K.C.G., C.J.K.); the Howard Hughes Medical Institute (to K.C.G., D.B.), the European Union's Horizon 2020 research and innovation program under grant agreement no. 668294 (to H.C.), and the NWO translational Adult Stem Cell Research grant 40-41400-98-1108 (to H.C.). | |
dc.language.iso | en | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.relation.ispartof | NATURE | |
dc.subject | ACTIVATION | |
dc.subject | AFFINITY | |
dc.subject | DYNAMICS | |
dc.subject | GROWTH | |
dc.subject | IN-VITRO EXPANSION | |
dc.subject | Multidisciplinary Sciences | |
dc.subject | PATHWAY | |
dc.subject | PROTEIN | |
dc.subject | REVEALS | |
dc.subject | Science & Technology - Other Topics | |
dc.subject | STEM-CELLS | |
dc.subject | STRUCTURAL BASIS | |
dc.title | Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling | |
dc.type | journal article | |
dc.identifier.doi | 10.1038/nature22306 | |
dc.identifier.isi | ISI:000400963800036 | |
dc.description.volume | 545 | |
dc.description.issue | 7653 | |
dc.description.startpage | 234+ | |
dc.contributor.orcid | 0000-0002-5261-5301 | |
dc.contributor.orcid | 0000-0002-7839-6397 | |
dc.contributor.orcid | 0000-0002-0319-9022 | |
dc.contributor.orcid | 0000-0002-7427-5985 | |
dc.contributor.orcid | 0000-0003-2266-5348 | |
dc.contributor.researcherid | A-3539-2013 | |
dc.contributor.researcherid | L-3901-2014 | |
dc.contributor.researcherid | K-2696-2017 | |
dc.identifier.eissn | 14764687 | |
dc.publisher.place | MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND | |
dcterms.isPartOf.abbreviation | Nature | |
dcterms.oaStatus | Green Accepted | |
crisitem.author.dept | Sonderforschungsbereich 944: Physiologie und Dynamik zellulärer Mikrokompartimente | - |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | organisation19 | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.orcid | 0000-0002-7839-6397 | - |
crisitem.author.orcid | 0000-0002-2143-2270 | - |
crisitem.author.parentorg | FB 05 - Biologie/Chemie | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.grandparentorg | Universität Osnabrück | - |
crisitem.author.netid | YoCh745 | - |
crisitem.author.netid | PiJa938 | - |
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geprüft am 18.05.2024