title: Erythropoietin: multiple targets, actions, and modifying influences for biological and clinical consideration.
abstract: Erythropoietin (EPO), a humoral regulator of erythropoiesis and replacement therapy for selected red blood cell disorders in EPO-deficient patients, has been implicated in a wide range of activities on diverse cell, tissue, and organ types. EPO signals via two receptors, one comprising EPO receptor (EPOR) homodimers and the other a heterodimer of EPOR and CD131-the common β chain component of the GM-CSF, interleukin (IL)-3, and IL-5 receptors. Ligation of EPORs triggers various signaling pathways, including the JAK2-STAT5 and MAPK-NF-κB pathways, depending both on the receptor and the target cell type. A new study in this issue reveals a novel EPO-triggered pathway involving a Spi2A serpin-lysosome-cathepsin cascade that is initiated through the homodimeric EPOR complex and is required for the survival of erythroid progenitors. A full understanding of EPO's effects on various cell types and their potential clinical relevance requires more work on the signaling events initiated through both EPORs, the effects of other cytokines and growth factors that modulate EPO's actions, and a comparison of the effects of full-length versus truncated forms of EPO.
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. hbroxmey@iupui.edu
authors: Hal E
authors: HE
authors: Broxmeyer
mesh_terms: D000818:Animals; D016207:Cytokines / Q000502:physiology; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000502:physiology; D004920:Erythropoiesis / Q000187:drug effects / Q000502:physiology; D004921:Erythropoietin / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D006402:Hematologic Diseases / Q000097:blood / Q000188:drug therapy; D006801:Humans; D017467:Receptors, Erythropoietin / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D016207:Cytokines; C554270:EPO protein, human; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin
references: J Physiol. 2011 Mar 15;589(Pt 6):1259-64
references: 21282290
references: Blood. 1991 May 15;77(10):2142-9
references: 1709371
references: Microbes Infect. 2012 Mar;14(3):238-46
references: 22094132
references: Immunity. 2002 Jun;16(6):815-25
references: 12121663
references: J Investig Med. 2011 Oct;59(7):1073-82
references: 20683348
references: Proc Natl Acad Sci U S A. 1987 Jun;84(11):3871-5
references: 3495800
references: J Exp Med. 2013 Feb 11;210(2):225-32
references: 23319700
references: Stem Cells Dev. 2010 Jan;19(1):1-4
references: 19886790
references: Science. 2004 Aug 13;305(5686):1000-3
references: 15310902
references: Nat Med. 2012 Dec;18(12):1786-96
references: 23160239
references: Biochim Biophys Acta. 2010 Aug;1806(1):82-95
references: 20406667
references: Immunity. 2011 Jan 28;34(1):61-74
references: 21256055
references: Cell Mol Neurobiol. 2011 Aug;31(6):931-7
references: 21538117
references: Blood. 2010 Nov 18;116(20):4045-59
references: 20974674
references: Curr Opin Hematol. 2010 May;17(3):169-76
references: 20173635
references: Kidney Int. 2006 Jul;70(2):246-50
references: 16738535
references: J Exp Med. 2010 Dec 20;207(13):2831-42
references: 21149549
references: Dev Biol. 2004 Dec 1;276(1):101-10
references: 15531367
references: Immunity. 2011 Jan 28;34(1):6-7
references: 21272782
references: J Immunol. 2002 Dec 15;169(12):7000-8
references: 12471135
references: Mol Cell. 2009 Jan 30;33(2):266-74
references: 19187767
references: Clin Cancer Res. 2011 Oct 15;17(20):6373-80
references: 21750199
references: Blood. 2008 Jun 1;111(11):5390-9
references: 18349318
references: Growth Factors. 2012 Feb;30(1):22-8
references: 22117584
references: Leuk Res. 2012 Aug;36(8):939-44
references: 22579365