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Cell. 2015 Mar 12;160(6):1196-208. doi: 10.1016/j.cell.2015.02.011. Epub 2015 Feb 26.

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

Author information

1
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.
2
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.
3
Division of Biophysics, Department of Biology, University of Osnabrück, 49076 Osnabrück, Germany.
4
Ludwig Institute for Cancer Research and de Duve Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
5
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.
6
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
7
DiscoveRx, 42501 Albrae Street, Fremont, CA 94538, USA.
8
Primity Bio, 3350 Scott Boulevard, Suite 6101, Santa Clara, CA 95054, USA.
9
Department of Computational Biology, Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK.
10
Institut Gustave Roussy, INSERM U1009, 94805 Villejuif, France.
11
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.

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.

PMID:
25728669
PMCID:
PMC4766813
DOI:
10.1016/j.cell.2015.02.011
[Indexed for MEDLINE]
Free PMC Article

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