Figure 1 - The BMPs bind to type I and II receptors and facilitate their association.

The constitutively active kinase domains of type II receptors phosphorylate type I receptors, and this in turn activates the SMAD signaling pathway through phosphorylation of receptor SMADs (SMAD1, SMAD5 and SMAD8). These associate with co-SMADs (SMAD4) to form a heteromeric complex that translocates to the nucleus and stimulates the expression of a wide range of target genes, including the gene encoding the iron regulatory peptide hepcidin. BMPs can also signal through SMAD-independent pathways, notably via MAP kinases. Dorsomorphin inhibits BMP signaling through the SMAD pathway, likely by affecting BMPR-I kinase activity. Many of the previously known inhibitors of BMP signaling (such as noggin and chordin) act upstream to sequester BMPs and cannot differentiate SMAD-dependent from SMAD-independent signaling. The activation of the hepcidin gene by IL-6 requires both the JAK-STAT and BMP-SMAD pathways, but how the pathways interact is unclear. Similarly, TfR2 and the HFE–TfR1 complex can alter hepcidin expression, but it is not known whether their functions require the BMP-SMAD system. Modified from ref. 10.