Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands
DC Element | Wert | Sprache |
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dc.contributor.author | Moraga, Ignacio | |
dc.contributor.author | Wernig, Gerlinde | |
dc.contributor.author | Wilmes, Stephan | |
dc.contributor.author | Gryshkova, Vitalina | |
dc.contributor.author | Richter, Christian P. | |
dc.contributor.author | Hong, Wan-Jen | |
dc.contributor.author | Sinha, Rahul | |
dc.contributor.author | Guo, Feng | |
dc.contributor.author | Fabionar, Hyna | |
dc.contributor.author | Wehrman, Tom S. | |
dc.contributor.author | Krutzik, Peter | |
dc.contributor.author | Demharter, Samuel | |
dc.contributor.author | Plo, Isabelle | |
dc.contributor.author | Weissman, Irving L. | |
dc.contributor.author | Minary, Peter | |
dc.contributor.author | Majeti, Ravindra | |
dc.contributor.author | Constantinescu, Stefan N. | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Garcia, K. Christopher | |
dc.date.accessioned | 2021-12-23T16:23:38Z | - |
dc.date.available | 2021-12-23T16:23:38Z | - |
dc.date.issued | 2015 | |
dc.identifier.issn | 00928674 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14611 | - |
dc.description.abstract | Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to ``tune'' signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems. | |
dc.description.sponsorship | BELSPO fellowship; de Duve Institute Delori postdoctoral fellowship; Training Program un Investigative Oncology [T32CA009287-35]; Stanford CIRM Training Program [TG2-01159]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U01HL099999]; FRS-FNRSFonds de la Recherche Scientifique - FNRS; Salus Sanguinis Foundation; Fondation contre le cancer (Belgium); Program IAP-BeMGI; Program ARCAustralian Research Council; Ludwig Institute; Howard Hughes Medical InstituteHoward Hughes Medical Institute; [NIH-RO1-AI51321]; Engineering and Physical Sciences Research CouncilUK Research & Innovation (UKRI)Engineering & Physical Sciences Research Council (EPSRC) [1231073] Funding Source: researchfish; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA086065, T32CA009287] Funding Source: NIH RePORTER; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [U01HL099999] 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) [R37AI051321, R01AI051321] Funding Source: NIH RePORTER; We thank Kevin Jude for technical assistance; the Division of Hematology Tissue Bank and the patients for donating their samples; Dr. William Vainchenker, Institut Gustave Roussy for providing patient JAK2V617F homozygous CD34+ cells; and Dr. Christian Pecquet for support with cell lines. This work was supported by the BELSPO and de Duve Institute Delori postdoctoral fellowships (V.G.), T32CA009287-35 (Training Program un Investigative Oncology) and TG2-01159 (Stanford CIRM Training Program) (to W.I.H.), NIH U01HL099999 (to G.W., R.S., and I.L.W.), FRS-FNRS, Salus Sanguinis Foundation, Fondation contre le cancer (Belgium), Programs IAP-BeMGI and ARC (S.N.C.), the Ludwig Institute (K.C.G.), NIH-RO1-AI51321 (K.C.G.), and the Howard Hughes Medical Institute (K.C.G.) | |
dc.language.iso | en | |
dc.publisher | CELL PRESS | |
dc.relation.ispartof | CELL | |
dc.subject | ACTIVATING MUTATION | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | Cell Biology | |
dc.subject | COMBINATORIAL ANTIBODY LIBRARIES | |
dc.subject | CRYSTAL-STRUCTURE | |
dc.subject | ERYTHROPOIETIN RECEPTOR | |
dc.subject | EXTRACELLULAR DOMAIN | |
dc.subject | HUMAN GROWTH-HORMONE | |
dc.subject | MONOCLONAL-ANTIBODIES | |
dc.subject | MYELOPROLIFERATIVE DISORDERS | |
dc.subject | THROMBOPOIETIN RECEPTOR | |
dc.subject | TYROSINE KINASE JAK2 | |
dc.title | Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands | |
dc.type | journal article | |
dc.identifier.doi | 10.1016/j.cell.2015.02.011 | |
dc.identifier.isi | ISI:000351951800018 | |
dc.description.volume | 160 | |
dc.description.issue | 6 | |
dc.description.startpage | 1196 | |
dc.description.endpage | 1208 | |
dc.contributor.orcid | 0000-0002-5915-6910 | |
dc.contributor.orcid | 0000-0002-8599-2699 | |
dc.contributor.orcid | 0000-0001-7352-3994 | |
dc.contributor.orcid | 0000-0002-4112-710X | |
dc.contributor.orcid | 0000-0001-9909-0701 | |
dc.contributor.researcherid | C-9056-2017 | |
dc.contributor.researcherid | AAT-6742-2021 | |
dc.identifier.eissn | 10974172 | |
dc.publisher.place | 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA | |
dcterms.isPartOf.abbreviation | Cell | |
dcterms.oaStatus | Bronze, 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 15.05.2024