Transmembrane Protein Aptamer Induces Cooperative Signaling by the EPO Receptor and the Cytokine Receptor β-Common Subunit
Li He,
Emily B. Cohen,
Anne P.B. Edwards,
Juliana Xavier-Ferrucio,
Katrine Bugge,
Ross S. Federman,
Devin Absher,
Richard M. Myers,
Birthe B. Kragelund,
Diane S. Krause,
Daniel DiMaio
Affiliations
Li He
Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005, USA
Emily B. Cohen
Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005, USA
Anne P.B. Edwards
Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005, USA
Juliana Xavier-Ferrucio
Department of Laboratory Medicine, Yale School of Medicine, P.O. Box 208073, New Haven, CT 06520-8073, USA
Katrine Bugge
Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), Department of Biology, University of Copenhagen, Copenhagen N 2200, Denmark
Ross S. Federman
Department of Immunobiology, Yale School of Medicine, P.O. Box 208011, New Haven, CT 06520-8011, USA
Devin Absher
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA
Richard M. Myers
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA
Birthe B. Kragelund
Structural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), Department of Biology, University of Copenhagen, Copenhagen N 2200, Denmark
Diane S. Krause
Department of Laboratory Medicine, Yale School of Medicine, P.O. Box 208073, New Haven, CT 06520-8073, USA; Yale Cancer Center, P.O. Box 208028, New Haven, CT 06520-8028, USA
Daniel DiMaio
Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005, USA; Department of Therapeutic Radiology, Yale School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040, USA; Department of Molecular Biophysics & Biochemistry, P.O. Box 208114, Yale University, New Haven, CT 06520-8114, USA; Yale Cancer Center, P.O. Box 208028, New Haven, CT 06520-8028, USA; Corresponding author
Summary: The erythropoietin receptor (EPOR) plays an essential role in erythropoiesis and other cellular processes by forming distinct signaling complexes composed of EPOR homodimers or hetero-oligomers between the EPOR and another receptor, but the mechanism of heteroreceptor assembly and signaling is poorly understood. We report here a 46-residue, artificial transmembrane protein aptamer, designated ELI-3, that binds and activates the EPOR and induces growth factor independence in murine BaF3 cells expressing the EPOR. ELI-3 requires the transmembrane domain and JAK2-binding sites of the EPOR for activity, but not the cytoplasmic tyrosines that mediate canonical EPOR signaling. Instead, ELI-3-induced proliferation and activation of JAK/STAT signaling requires the transmembrane and cytoplasmic domains of the cytokine receptor β-common subunit (βcR) in addition to the EPOR. Moreover, ELI-3 fails to induce erythroid differentiation of primary human hematopoietic progenitor cells but inhibits nonhematopoietic cell death induced by serum withdrawal. : Biological Sciences; Cell Biology; Functional Aspects of Cell Biology Subject Areas: Biological Sciences, Cell Biology, Functional Aspects of Cell Biology
