Model of crosstalk between erythropoiesis and iron metabolism involving TGF-β family member GDF11. Erythroid precursor proliferation and differentiation is regulated in part by multiple members of the TGF-β family. GDF11 binding to ActRII results in Smad2,3 phosphorylation and leads to the expansion of erythroid precursors and suppresses differentiation, resulting in ineffective erythropoiesis and iron overload. Hepcidin expression in hepatocytes is stimulated through the iron pathway (through bone morphogenic protein receptor signaling and Smad1,5,8 phosphorylation) and suppressed through the erythropoiesis pathway (possibly through ERFE binding and signaling through a yet-unidentified receptor). ActRII, activin receptor IIa; BMP6, bone morphogenic protein 6; BMPR, bone morphogenic protein receptor; GDF11, growth differentiation factor 11; R-Smad, receptor-mediated decapentaplegic protein; R-Smad-P, phosphorylated R-Smad.