Format

Send to

Choose Destination
iScience. 2019 Jul 26;17:167-181. doi: 10.1016/j.isci.2019.06.027. Epub 2019 Jun 21.

Transmembrane Protein Aptamer Induces Cooperative Signaling by the EPO Receptor and the Cytokine Receptor β-Common Subunit.

Author information

1
Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005, USA.
2
Department of Laboratory Medicine, Yale School of Medicine, P.O. Box 208073, New Haven, CT 06520-8073, USA.
3
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.
4
Department of Immunobiology, Yale School of Medicine, P.O. Box 208011, New Haven, CT 06520-8011, USA.
5
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
6
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.
7
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. Electronic address: daniel.dimaio@yale.edu.

Abstract

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.

KEYWORDS:

Biological Sciences; Cell Biology; Functional Aspects of Cell Biology

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center