Intersection of erythropoietin signaling, apoptotic pathways, and molecular chaperones during erythropoiesis. Erythropoietin (Epo) promotes erythroblast survival and maturation. Caspase activation, initiated in part through Epo-induced mitochondrial depolarization (ψΔΜ), is essential for erythroid maturation. Hsp70 inhibits apoptosis by binding cytoplasmic apoptosis initiating factor (AIF), inhibiting its accumulation in the nucleus. In addition, Epo signaling causes Hsp70 to translocate to the nucleus and bind the essential transcription factor GATA-1 to inhibit its cleavage by activated caspase 3. Erythropoietin signaling also induces expression of HSPA9B/mortalin, a mitochondrial Hsp70-like protein that inhibits apoptosis, in part by suppressing the production of reactive oxygen species (ROS). Professional illustration by Paulette Dennis.