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

TY - JOUR

T1 - Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands

AU - Moraga, Ignacio

AU - Wernig, Gerlinde

AU - Wilmes, Stephan

AU - Gryshkova, Vitalina

AU - Richter, Christian P.

AU - Hong, Wan-Jen

AU - Sinha, Rahul

AU - Guo, Feng

AU - Fabionar, Hyna

AU - Wehrman, Tom S.

AU - Krutzik, Peter

AU - Demharter, Samuel

AU - Plo, Isabelle

AU - Weissman, Irving L.

AU - Minary, Peter

AU - Majeti, Ravindra

AU - Constantinescu, Stefan N.

AU - Piehler, Jacob

AU - Garcia, K. Christopher

PY - 2015/3/12

Y1 - 2015/3/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84925535544

U2 - 10.1016/j.cell.2015.02.011

DO - 10.1016/j.cell.2015.02.011

M3 - Article

C2 - 25728669

AN - SCOPUS:84925535544

SN - 0092-8674

VL - 160

SP - 1196

EP - 1208

JO - Cell

JF - Cell

IS - 6

ER -