FIGURE 1.

Sensing of transferrin-bound iron and regulation of hepcidin expression in hepatocytes. The iron-sensing process involves binding of transferrin-bound iron to TfR1 causing a dissociation of Hfe from the Hfe/TfR1 partnership, relocation of Hfe to TfR2 and presumably the formation of a large membrane-bound complex composed of Hfe/TfR2/Hjv and BMPRII and I. This hepatocyte-membrane complex activates transduction cascade involving the phosphorylation of the Smad1/5/8 and subsequent binding of common Smad4 protein to form a transcriptional complex which directly activates hepcidin transcription. The Bmp/Smad signaling is the central pathway for the regulation of hepcidin transcription. Lack of Hfe and other components of the membrane-bound complex severely impair the phosphorylation of Smad1/5/8 and consequently the transcription of hepcidin. Combined deficiency of Hfe and TfR2 results in decreased Erk/Mapk signaling activity in the liver, implicating that additional or parallel signaling pathway to Bmp/Smad may be involved in the control of hepatic hepcidin transcription.