A model for the function of hepatic and erythroid TfR2 in the control of systemic iron metabolism and erythropoiesis. (A) In an iron-replete state, stabilized TfR2 induces iron signaling to hepcidin in the liver and impairs Epo sensitivity in erythroid cells. (B) In an iron-deficient state, TfR2 destabilization prevents iron signaling to hepcidin in the liver and allows enhanced Epo sensitivity in erythroid cells.