Erythropoietin Receptor Signaling and Lipid Rafts

Erythropoiesis is tightly regulated by the growth factor erythropoietin (Epo). Signal activation begins when Epo engages its cognate receptor, Epo-R, triggering receptor homodimerization, and recruitment of signaling intermediates including Jak2 that phosphorylates both the receptor cytoplasmic tail and downstream effectors including the transcription factor, STAT5. Transcription factors subsequently activate transcription of prosurvival and prodifferentiation genes responsible for red blood cell production. The fidelity of Epo-R signaling is dependent upon residence within detergent insoluble membrane lipid raft fractions. Lipid rafts are membrane microdomains that serve as signaling scaffolds composed of densely packed sphingolipids and cholesterol where receptors and intermediate signaling proteins are recruited and interact to execute stimuli. Disruption of lipid rafts is detrimental to Epo signaling, a phenomenon that may be utilized to design novel therapeutics for conditions in which Epo signaling is deficient. Here, we review the Epo signaling cascade, particularly, as it relates to localization and dependence on lipid rafts, and discuss considerations for novel therapeutic design.