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.
Original language | English |
---|---|
Pages (from-to) | 1196-1208 |
Number of pages | 13 |
Journal | Cell |
Volume | 160 |
Issue number | 6 |
Early online date | 26 Feb 2015 |
DOIs | |
Publication status | Published - 12 Mar 2015 |
Fingerprint
Dive into the research topics of 'Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands'. Together they form a unique fingerprint.Profiles
-
Moraga Gonzalez, Ignacio
- Cell Signalling and Immunology - Reader (Teaching and Research)
Person: Academic