Iron-dependent BMP signaling. Transferrin receptor 1 (TFR1), the autosomal recessive hereditary hemochromatosis proteins HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV) as well as the bone morphogenetic protein receptor type I and II (BMPR I/II) complex are associated with the cell surface. HFE associates with TFR1 and TFR2 in an equilibrium modified by the concentration of holotransferrin (TF). It has been suggested that HFE and TFR2 can further associate with the HJV-BMPR I/II signaling complex to modify BMPR signaling mediated by phosphorylation upon sons of mothers against decapentaplegic homologues (SMADs) 1, 5, and 8. Association of phosphorylated SMAD1/5/8 with a common co-SMAD, SMAD4, leads to translocation of the complex into the nucleus and stimulation of hepcidin (HAMP) gene expression.