Applying a homology search method previously described, we identified a sequence in the extracellular dimerization site of the erythropoietin receptor, distant from the hormone binding site. A peptide identical to that sequence was synthesized. Remarkably, it activated receptor signaling in the absence of erythropoietin. Neither the peptide nor the hormone altered the affinity of the other for the receptor; thus, the peptide does not bind to the hormone binding site. The combined activation of signal transduction by hormone and peptide was strongly synergistic. In mice, the peptide acted like the hormone, protecting against the decrease in hematocrit caused by carboplatin.We previously had described a method for identifying peptides that would selectively inhibit internalization of insulin, insulinlike growth factor 1, and other receptors (1-3). We used the same MHC class I protein (MHC-I) sequence D k -(61-85) as probe in a homology search with the erythropoietin (EPO) receptor (EPO-R) as target. We identified a homologous sequence in the extracellular domain of the receptor, distant from the hormone binding site, in a region suggested to participate in dimerization (4). An EPO-R-derived peptide (ERP) was synthesized identical to that sequence. Now we describe the wholly unexpected finding that EPO-R, which normally is activated by hormone-induced dimerization, can be activated by ERP in the absence of hormone. The peptide does not bind to the hormone binding site; it apparently complexes with its identical sequence in the homology domain. Interestingly, EPO and ERP together produce a dramatic synergy of effect. Finally, we show that in mice ERP has the same effect as EPO.
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