BACKGROUND: Impaired regulation of hepcidin in response to iron is the cause of 
genetic hemochromatosis associated with defects of HFE and transferrin receptor 
2. However, the role of these proteins in the regulation of hepcidin expression 
is unclear.
DESIGN AND METHODS: Hepcidin expression, SMAD and extracellular signal-regulated 
kinase (Erk) phosphorylation and furin expression were analyzed in hepatic HepG2 
cells in which HFE and transferrin receptor 2 were down-regulated or expressed, 
or furin activity specifically inhibited. Furin expression was also analyzed in 
the liver of transferrin receptor 2 null mice.
RESULTS: We showed that the silencing of HFE and transferrin receptor 2 reduced 
both Erk phosphorylation and furin expression, that the exogenous expression of 
the two enhanced the induction of phosphoErk1/2 and furin by holotransferrin, 
but that this did not occur when the pathogenic HFE mutant C282Y was expressed. 
Furin, phosphoErk1/2 and phosphoSMAD1/5/8 were down-regulated also in 
transferrin receptor 2-null mice. Treatment of HepG2 cells with an inhibitor of 
furin activity caused a strong suppression of hepcidin mRNA, probably due to the 
inhibition of bone morphogenic protein maturation.
CONCLUSIONS: The data indicate that transferrin receptor 2 and HFE are involved 
in holotransferrin-dependent signaling for the regulation of furin which 
involved Erk phosphorylation. Furin in turn may control hepcidin expression.