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

Journal article

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.

Authors: Moraga, I; Wernig, G; Wilmes, S; Gryshkova, V; Richter, C

• Publication status: Published
• Peer review status: Peer reviewed
• Journal: Cell
• Volume: 160
• Issue: 6
• Pages: 1196-1208
• Publication date: 2015-03-01
• DOI: 10.1016/j.cell.2015.02.011
• ISSN: 0092-8674
• Language: English