Abstract
Erythropoietin (EPO) is a clinically significant four-helical cytokine, exhibiting erythropoietic, cytoprotective, immunomodulatory, and cancer-promoting activities. Despite vast knowledge on its signaling pathways and physiological effects, extracellular factors regulating EPO activity remain underexplored. Here we show by surface plasmon resonance spectroscopy, that among eighteen members of Ca2+-binding proteins of the S100 protein family studied, only S100A2, S100A6 and S100P proteins specifically recognize EPO with equilibrium dissociation constants ranging from 81 nM to 0.5 µM. The interactions occur exclusively under calcium excess. Bioinformatics analysis showed that the EPO-S100 interactions could be relevant to progression of neoplastic diseases, including cancer, and other diseases. The detailed knowledge of distinct physiological effects of the EPO-S100 interactions could favor development of more efficient clinical implications of EPO. Summing up our data with previous findings, we conclude that S100 proteins are potentially able to directly affect functional activities of specific members of all families of four-helical cytokines, and cytokines of other structural superfamilies.
Highlights
Erythropoietin (EPO) is a pleiotropic monomeric glycosylated short-chain four-helical cytokine (SCOP entry 4000852; newly synthesized EPO is the 193-residue long protein containing a 27-residue long signal peptide, which is removed upon maturation, giving rise to 166 residues in mature form, 30.4 kDa), mainly produced by adult kidney type I
EPO signals through homodimer of the EPO receptor (EPOR), the heterodimer of the EPOR and the β common receptor (CD131, βcR) or the Ephrin type-B receptor 4 (EphB4) [6,7,8,9]
It serves a tissue-protective role upon binding to the EPOR and the βcR receptors, which activates STAT3, MAPK and PI3K/Akt pathways, leading to immunosuppression and inhibition of apoptosis, inflammation and fibrosis [7]
Summary
Erythropoietin (EPO) is a pleiotropic monomeric glycosylated short-chain four-helical cytokine (SCOP entry 4000852; newly synthesized EPO is the 193-residue long protein containing a 27-residue long signal peptide, which is removed upon maturation, giving rise to 166 residues in mature form, 30.4 kDa), mainly produced by adult kidney type I interstitial cells, fetal liver hepatocytes, and Ito cells [1,2,3,4,5]. EPO stimulates basal and stress-induced erythropoiesis (in the case of bleeding, hypoxia, etc.) via binding to the EPOR on the erythroid progenitor surface, thereby triggering STAT5, Ras/MAPK and PI3K/Akt pathways, which drive expression of the genes promoting cell survival, proliferation and maturation, along with feedback inhibition of the EPOR signaling [6]. EPO affects multipotent mesenchymal stem cells, which leads to bone remodeling, induction of angiogenesis and secretion of trophic factors [3]. It serves a tissue-protective role upon binding to the EPOR and the βcR receptors (co-expressed upon tissue injury in kidney, liver, heart and nervous system), which activates STAT3, MAPK and PI3K/Akt pathways, leading to immunosuppression and inhibition of apoptosis, inflammation and fibrosis [7].
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