Erythropoietins: A common mechanism of action

Erythropoiesis. BFUe=burst-forming unit–erythroid; CFUe=colony-forming unit–erythroid; Epo=erythropoietin; FLK=fetal liver kinase; FLT=fetal liver tyrosine kinase; G-CSF=granulocyte-colony stimulating factor; GEMM=granulocyte, erythrocyte, monocyte, megakaryocyte; GM-CSF=granulocyte macrophage CSF; IL=interleukin; MIP=macrophage inflammatory protein; SCF=stem cell factor; TGF=transforming growth factor; TPO=thrombopoietin.

The nuclear magnetic resonance minimized average structure of human erythropoietin.

Disproportion between half-life of recombinant human erythropoietin and lifespan of red blood cells. MEC=minimum effective dose. Adapted from Molineux [108] with permission.

Signal transduction pathways of the erythropoietin receptor. Binding of erythropoietin (EPO) causes conformational changes to the EPO receptor, transphosphorylation of associated JAK2 molecules, phosphorylation of tyrosine residues in the cytoplasmic tail of the receptor, and phosphorylation or activation of signaling molecules. Phosphorylation of signal transducers and activators of transcription (STAT) 5 transcription factor (TF) causes homodimerization, translocation to the nucleus, and activation of genes for antiapoptotic molecules. Phosphorylated phosphatidylinositol 3-kinase (PI-3 kinase) phosphorylates protein kinase B (PKB)/Akt. PKB/Akt: 1) phosphorylates and inactivates proapoptotic molecules (Bad, caspase 9 or glycogen synthase kinase-3b [GSK-3b]); 2) phosphorylates FOXO TF, inhibiting translocation to the nucleus and activation of target genes (Fas ligand, Bim); and 3) phosphorylates IκB, allowing the release of the transcription factor nuclear factor (NF)-κB that then translocates into the nucleus and activates target genes encoding antiapoptotic molecules (XIAP, c-IAP2). Binding of EPO to its receptor also activates Hsp70, which binds to and inactivates proapoptotic molecules (apoptosis protease-activating factor-1 [Apaf-1], apoptosis-inducing factor [AIF]).

Molecular structures of rhEPO (A) and darbepoetin alfa (B). Reprinted by permission from Macmillan Publishers Ltd: Nature Biotechnology [7], 2003. rhEPO=recombinant human erythropoietin.