Apoptosis-inducing anti-HER2 agents operate through oligomerization-induced receptor immobilization
DC Element | Wert | Sprache |
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dc.contributor.author | Stuber, Jakob C. | |
dc.contributor.author | Richter, Christian P. | |
dc.contributor.author | Bellon, Junel Sotolongo | |
dc.contributor.author | Schwill, Martin | |
dc.contributor.author | Konig, Iwo | |
dc.contributor.author | Schuler, Benjamin | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Plueckthun, Andreas | |
dc.date.accessioned | 2021-12-23T16:18:32Z | - |
dc.date.available | 2021-12-23T16:18:32Z | - |
dc.date.issued | 2021 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/12732 | - |
dc.description.abstract | Overexpression of the receptor tyrosine kinase HER2 plays a critical role in the development of various tumors. Biparatopic designed ankyrin repeat proteins (bipDARPins) potently induce apoptosis in HER2-addicted breast cancer cell lines. Here, we have investigated how the spatiotemporal receptor organization at the cell surface is modulated by these agents and is distinguished from other molecules, which do not elicit apoptosis. Binding of conventional antibodies is accompanied by moderate reduction of receptor mobility, in agreement with HER2 being dimerized by the bivalent IgG. In contrast, the most potent apoptosis-inducing bipDARPins lead to a dramatic arrest of HER2. Dual-color single-molecule tracking revealed that the HER2 ``lockdown'' by these bipDARPins is caused by the formation of HER2-DARPin oligomer chains, which are trapped in nanoscopic membrane domains. Our findings establish that efficient neutralization of receptor tyrosine kinase signaling can be achieved through intermolecular bipDARPin crosslinking alone, resulting in inactivated, locked-down bipDARPin-HER2 complexes. Stuber et. al. show that receptor tyrosine kinase signaling can be neutralized through intermolecular, biparatopic bipDARPin crosslinking that locks down the bipDARPin-HER2 complexes. This affects the spatiotemporal organization and dynamics of HER2 in the plasma membrane. | |
dc.description.sponsorship | DFGGerman Research Foundation (DFG)European Commission [PI 405/14-1]; Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission [310030_192689]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 944]; We thank Dr. Christoph Klenk for support during the initial set-up of FRAP microscopy and Dr. Daniel Nettels for help with confocal instrumentation and data analysis. Dr. Christian Jost and Florian Kast are acknowledged for providing and helping with the purification of some DARPin constructs, respectively, and Lukas Becker for helping with sample shipments. Flow cytometry and imaging were performed with equipment maintained by the Flow Cytometry Facility (FCF) and the Center for Microscopy and Image Analysis (ZMB) of the University of Zurich. Single-molecule TIRF microscopy and image analysis was performed with support of the DFG-funded Integrated Bioimaging Facility Osnabruck iBiOs (PI 405/14-1). This work was supported by the Swiss National Science Foundation to B.S and by grant 310030_192689 (to A.P.) and by the Deutsche Forschungsgemeinschaft (SFB 944, Z) to J.P. | |
dc.language.iso | en | |
dc.publisher | NATURE RESEARCH | |
dc.relation.ispartof | COMMUNICATIONS BIOLOGY | |
dc.subject | BINDING-PROTEINS | |
dc.subject | Biology | |
dc.subject | BREAST-CANCER | |
dc.subject | DIMERIZATION | |
dc.subject | GROWTH-FACTOR RECEPTOR | |
dc.subject | HER2 | |
dc.subject | Life Sciences & Biomedicine - Other Topics | |
dc.subject | Multidisciplinary Sciences | |
dc.subject | ORGANIZATION | |
dc.subject | PLASMA-MEMBRANE | |
dc.subject | Science & Technology - Other Topics | |
dc.subject | SIGNAL-TRANSDUCTION | |
dc.subject | SINGLE-MOLECULE TRACKING | |
dc.subject | STRUCTURAL BASIS | |
dc.title | Apoptosis-inducing anti-HER2 agents operate through oligomerization-induced receptor immobilization | |
dc.type | journal article | |
dc.identifier.doi | 10.1038/s42003-021-02253-4 | |
dc.identifier.isi | ISI:000664956200002 | |
dc.description.volume | 4 | |
dc.description.issue | 1 | |
dc.contributor.orcid | 0000-0002-5970-4251 | |
dc.contributor.orcid | 0000-0002-3406-0664 | |
dc.contributor.orcid | 0000-0003-4191-5306 | |
dc.contributor.orcid | 0000-0002-2798-5490 | |
dc.contributor.researcherid | E-7342-2011 | |
dc.contributor.researcherid | C-2746-2009 | |
dc.identifier.eissn | 23993642 | |
dc.publisher.place | HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY | |
dcterms.isPartOf.abbreviation | Commun. Biol. | |
dcterms.oaStatus | gold, Green Published, Green Accepted | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.orcid | 0000-0002-2143-2270 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | PiJa938 | - |
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geprüft am 16.05.2024