Figure 10.

Proposed model for activin B-mediated hepcidin regulation in hepatocytes. Under inflammatory conditions, activin B expression is stimulated in the liver and binds to its canonical type II receptors ACVR2A and ACVR2B, which can recruit either its canonical type I receptor ALK7 to stimulate SMAD2/3 phosphorylation or noncanonical BMP type I receptors ALK2 and ALK3 and the coreceptor HJV to stimulate SMAD1/5/8 phosphorylation. Iron regulates SMAD1/5/8 phosphorylation through BMP6, which activates a similar receptor complex that differs only in type II receptor utilization. Phosphorylated SMAD1/5/8 stimulated by activin B or BMP6 complexes with common mediator SMAD4 to stimulate hepcidin transcription. Activin A signals in hepatocytes via ACVR2B and ALK4 to stimulate SMAD2/3 phosphorylation, which does not stimulate hepcidin expression.