Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands.

Autor:	Moraga I; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5345, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA., Wernig G; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305-5345, USA; Department of Pathology, Division of Hematopathology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA., Wilmes S; Division of Biophysics, Department of Biology, University of Osnabrück, 49076 Osnabrück, Germany., Gryshkova V; Ludwig Institute for Cancer Research and de Duve Institute, Université catholique de Louvain, 1200 Brussels, Belgium., Richter CP; Division of Biophysics, Department of Biology, University of Osnabrück, 49076 Osnabrück, Germany., Hong WJ; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305-5345, USA; Department of Internal Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA., Sinha R; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305-5345, USA., Guo F; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5345, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA., Fabionar H; DiscoveRx, 42501 Albrae Street, Fremont, CA 94538, USA., Wehrman TS; Primity Bio, 3350 Scott Boulevard, Suite 6101, Santa Clara, CA 95054, USA., Krutzik P; Primity Bio, 3350 Scott Boulevard, Suite 6101, Santa Clara, CA 95054, USA., Demharter S; Department of Computational Biology, Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK., Plo I; Institut Gustave Roussy, INSERM U1009, 94805 Villejuif, France., Weissman IL; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305-5345, USA., Minary P; Department of Computational Biology, Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK., Majeti R; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305-5345, USA; Department of Internal Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA., Constantinescu SN; Ludwig Institute for Cancer Research and de Duve Institute, Université catholique de Louvain, 1200 Brussels, Belgium., Piehler J; Division of Biophysics, Department of Biology, University of Osnabrück, 49076 Osnabrück, Germany., Garcia KC; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5345, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA. Electronic address: kcgarcia@stanford.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2015 Mar 12; Vol. 160 (6), pp. 1196-208. Date of Electronic Publication: 2015 Feb 26.
DOI:	10.1016/j.cell.2015.02.011
Abstrakt:	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. (Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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