EPO does not promote interaction between the erythropoietin and beta-common receptors

Shing, Karen S. Cheung Tung; Broughton, Sophie E.; Nero, Tracy L.; Gillinder, Kevin R.; Ilsley, Melissa; Ramshaw, Hayley S.; Lopez, Angel F.; Griffin, Michael D. W.; Parker, Michael W.; Perkins, Andrew C.; Dhagat, Urmi

doi:10.1038/s41598-018-29865-x

Cited by 21 publications

(17 citation statements)

References 60 publications

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“…Furthermore, cardioprotection in mice by darbepoetin, a long acting derivative of EPO, did not require the βc receptor (Kanellakis et al, 2010). Biophysical analyses show that the extracellular domains of EPOR and the βc receptor do not directly interact in the presence or absence of EPO (Cheung Tung Shing et al, 2018), and the role of the βc receptor in EPOR response to EPO remains uncertain. Other proposed EPO binding receptors include the Ephrin B4 receptor on cancer cells and the orphan cytokine receptor CRLF3 on insect neural cells (Pradeep et al, 2015;Hahn et al, 2017).…”

Section: Alternate Epo Receptors and Epo Derivativesmentioning

confidence: 99%

The Many Facets of Erythropoietin Physiologic and Metabolic Response

2020

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Section: Alternate Epo Receptors and Epo Derivativesmentioning

confidence: 99%

The Many Facets of Erythropoietin Physiologic and Metabolic Response

2020

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“…Although there is robust data associating IRR activity with EPO’s tissue protective effects, 23 there is currently insufficient evidence establishing that the IRR mediates EPO’s behavioral effects in the CNS. 24 , 25 Our understanding that QPO, and by extension CEPO, binds AS1 as strongly as EPO indicates that at least one half of the IRR complex involves EPO bound to AS1 of an EPOR monomer. In addition, it also implies that the residues of EPO associated with AS2 might not play a significant role.…”

Section: Discussionmentioning

confidence: 99%

<p>Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor</p>

Pekas¹,

Petersen²,

Sathyanesan³

et al. 2020

DDDT

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Introduction: Carbamoylated erythropoietin (CEPO) is a chemically engineered, nonhematopoietic derivative of erythropoietin (EPO) that retains its antidepressant and procognitive effects, which are attributed to the increased expression of neurotrophic factors like brain derived neurotrophic factor (BDNF), in the central nervous system. However, the chemical modification process which produces CEPO from erythropoietin (EPO) requires pure EPO as raw material, is challenging to scale-up and can also cause batch-to-batch variability. To address these key limitations while retaining its behavioral effects, we designed, expressed and analyzed a triple, glutamine, substitution recombinant mimetic of CEPO, named QPO. Methods and Materials: We employ a combination of computational structural biology, molecular, cellular and behavioral assays to design, produce, purify and test QPO. Results: QPO was shown to be a nonhematopoietic polypeptide with significant antidepressant-like and pro-cognitive behavioral effects in rodent assays while significantly upregulating BDNF expression in-vitro and in-vivo. The in-silico binding affinity analysis of QPO bound to the EPOR/EPOR homodimer receptor shows significantly decreased binding to Active Site 2, but not Active Site 1, of EPOR. Discussion: The results of the behavioral and gene expression analysis imply that QPO is a successful CEPO mimetic protein and potentially acts via a similar neurotrophic mechanism, making it a drug development target for psychiatric disorders. The decreased binding to Active Site 2 could imply that this active site is not involved in neuroactive signaling and could allow the development of a functional innate repair receptor (IRR) model. Substituting the three glutamine substitution residues with arginine (RPO) resulted in the loss of behavioral activity, indicating the importance of glutamine residues at those positions.

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“…First, little if any of the cytoplasmic domain of either receptor is required for heteroreceptor formation in the absence of ELI-3, but the TMDs of both proteins are required. In addition, the extracellular domains of the EPOR and βcR do not physically interact in vitro (Cheung Tung Shing et al., 2018). These findings suggest that the TMD and/or the TMD-proximal segments of the EPOR and βcR mediate heteroreceptor formation.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that the tissue-protective effect of EPO is mediated by an EPOR/βcR heteroreceptor, and not by EPOR homodimerization (Bohr et al., 2015). However, the role of the heteroreceptor in tissue protection remains controversial (see citations in Cheung Tung Shing et al. 2018), and in some situations a classical EPOR homodimer can provide a protective signal (Um et al., 2007).…”

Section: Introductionmentioning

confidence: 99%

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

Cohen

Edwards

et al. 2019

iScience

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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.

show abstract

EPO does not promote interaction between the erythropoietin and beta-common receptors

Cited by 21 publications

References 60 publications

The Many Facets of Erythropoietin Physiologic and Metabolic Response

The Many Facets of Erythropoietin Physiologic and Metabolic Response

<p>Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor</p>

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

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