| |  Online-Ressource |
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| Verfasst von: | Sun, Rui [VerfasserIn]  |
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| | Meng, Zibo [VerfasserIn] |
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| | Lee, Hyeyoon [VerfasserIn] |
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| | Offringa, Rienk [VerfasserIn] |
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| | Niehrs, Christof [VerfasserIn] |
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| Titel: | ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation |
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| Verf.angabe: | Rui Sun, Zibo Meng, Hyeyoon Lee, Rienk Offringa, and Christof Niehrs |
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| E-Jahr: | 2023 |
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| Jahr: | 20 July 2023 |
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| Umfang: | 23 S. |
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| Fussnoten: | Online verfügbar: 14. Juni 2023, Artikelversion: 20. Juli 2023 ; Gesehen am 04.10.2023 |
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| Titel Quelle: | Enthalten in: Cell chemical biology |
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| Ort Quelle: | Amsterdam : Elsevier, 2016 |
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| Jahr Quelle: | 2023 |
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| Band/Heft Quelle: | 30(2023), 7 vom: Juli, Seite 739-752.e8 |
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| ISSN Quelle: | 2451-9448 |
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| Abstract: | Proteolysis-targeting chimeras (PROTACs) are an emerging technology for therapeutic intervention, but options to target cell surface proteins and receptors remain limited. Here we introduce ROTACs, bispecific WNT- and BMP-signaling-disabled R-spondin (RSPO) chimeras, which leverage the specificity of these stem cell growth factors for ZNRF3/RNF43 E3 transmembrane ligases, to target degradation of transmembrane proteins. As a proof-of-concept, we targeted the immune checkpoint protein, programmed death ligand 1 (PD-L1), a prominent cancer therapeutic target, with a bispecific RSPO2 chimera, R2PD1. The R2PD1 chimeric protein binds to PD-L1 and at picomolar concentration induces its lysosomal degradation. In three melanoma cell lines, R2PD1 induced between 50 and 90% PD-L1 protein degradation. PD-L1 degradation was strictly dependent on ZNRF3/RNF43. Moreover, R2PD1 reactivates cytotoxic T cells and inhibits tumor cell proliferation more potently than Atezolizumab. We suggest that signaling-disabled ROTACs represent a paradigm to target cell surface proteins for degradation in a range of applications. |
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| DOI: | doi:10.1016/j.chembiol.2023.05.010 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext: https://doi.org/10.1016/j.chembiol.2023.05.010 |
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| | Volltext: https://www.sciencedirect.com/science/article/pii/S2451945623001538 |
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| | DOI: https://doi.org/10.1016/j.chembiol.2023.05.010 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | lysosome |
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| | LYTAC |
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| | PD-L1 |
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| | PROTAC |
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| | protein degradation |
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| | R-spondin |
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| | RNF43 |
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| | transmembrane E3 ligase |
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| | ZNRF3 |
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| K10plus-PPN: | 1860681042 |
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| Verknüpfungen: | → Zeitschrift |
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ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation / Sun, Rui [VerfasserIn]; 20 July 2023 (Online-Ressource)
