Transferrin receptor 2 and HFE regulate furin expression via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) signaling. Implications for transferrin-dependent hepcidin regulation.

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.