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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.

Original publication

DOI

10.1016/j.cell.2015.02.011

Type

Journal article

Journal

Cell

Publication Date

12/03/2015

Volume

160

Pages

1196 - 1208

Keywords

Amino Acid Sequence, Animals, Antibodies, Monoclonal, Cell Line, Crystallography, X-Ray, Dimerization, Erythropoietin, Humans, Janus Kinase 2, Mice, Models, Molecular, Molecular Dynamics Simulation, Molecular Sequence Data, Point Mutation, Protein Engineering, Receptors, Erythropoietin, Sequence Alignment, Signal Transduction