Journal
CELL
Volume 160, Issue 6, Pages 1196-1208Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.02.011
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Funding
- BELSPO fellowship
- de Duve Institute Delori postdoctoral fellowship
- Training Program un Investigative Oncology [T32CA009287-35]
- Stanford CIRM Training Program [TG2-01159]
- NIH [U01HL099999]
- FRS-FNRS
- Salus Sanguinis Foundation
- Fondation contre le cancer (Belgium)
- Program IAP-BeMGI
- Program ARC
- Ludwig Institute
- Howard Hughes Medical Institute
- [NIH-RO1-AI51321]
- Engineering and Physical Sciences Research Council [1231073] Funding Source: researchfish
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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.
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