He Li, Cohen Emily B, Edwards Anne P B, Xavier-Ferrucio Juliana, Bugge Katrine, Federman Ross S, Absher Devin, Myers Richard M, Kragelund Birthe B, Krause Diane S, DiMaio Daniel
Department of Genetics, Yale School of Medicine, P.O. Box 208005, New Haven, CT 06520-8005, USA.
Department of Laboratory Medicine, Yale School of Medicine, P.O. Box 208073, New Haven, CT 06520-8073, USA.
iScience. 2019 Jul 26;17:167-181. doi: 10.1016/j.isci.2019.06.027. Epub 2019 Jun 21.
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.
促红细胞生成素受体（EPOR）通过形成由EPOR同二聚体或EPOR与另一种受体之间的异源寡聚体组成的独特信号复合物，在红细胞生成和其他细胞过程中发挥重要作用，但异源受体组装和信号传导的机制尚不清楚。我们在此报告一种由46个氨基酸残基组成的人工跨膜蛋白适体，命名为ELI-3，它能结合并激活EPOR，并在表达EPOR的小鼠BaF3细胞中诱导生长因子非依赖性。ELI-3发挥活性需要EPOR的跨膜结构域和JAK2结合位点，但不需要介导经典EPOR信号传导的胞质酪氨酸。相反，ELI-3诱导的增殖和JAK/STAT信号传导激活除了需要EPOR外，还需要细胞因子受体β共同亚基（βcR）的跨膜和胞质结构域。此外，ELI-3不能诱导原代人类造血祖细胞的红系分化，但能抑制血清剥夺诱导的非造血细胞死亡。
