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.


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.
Poli
Maura
M
Dipartimento Materno Infantile e Tecnologie Biomediche, Facoltà di Medicina e Chirurgia, Università di Brescia, 25123 Brescia, Italy.
Luscieti
Sara
S
Gandini
Valentina
V
Maccarinelli
Federica
F
Finazzi
Dario
D
Silvestri
Laura
L
Roetto
Antonella
A
Arosio
Paolo
P
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D056945:Hep G2 Cells; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000502:physiology; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000235:genetics / Q000378:metabolism*
D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C103673:HFE protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D051785:Smad Proteins; C503640:TFR2 protein, human; C503641:TFR2 protein, mouse; D014168:Transferrin; D020929:Mitogen-Activated Protein Kinase Kinases; C468731:FURIN protein, human; D045683:Furin