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

• Published in: Haematologica (Roma) Vol. 95; no. 11; pp. 1832 - 1840
• Main Authors: POLI, Maura, LUSCIETI, Sara, GANDINI, Valentina, MACCARINELLI, Federica, FINAZZI, Dario, SILVESTRI, Laura, ROETTO, Antonella, AROSIO, Paolo
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01.11.2010
• Subjects: Animals; Antimicrobial Cationic Peptides - biosynthesis; Antimicrobial Cationic Peptides - genetics; Biological and medical sciences; Furin - genetics; Furin - metabolism; Gene Expression Regulation - physiology; Hematologic and hematopoietic diseases; Hemochromatosis - genetics; Hemochromatosis - metabolism; Hemochromatosis Protein; Hep G2 Cells; Hepcidins; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Humans; MAP Kinase Signaling System - physiology; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - metabolism; Mutation; Original; Phosphorylation - physiology; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; Smad Proteins - genetics; Smad Proteins - metabolism; Transferrin - genetics; Transferrin - metabolism; Transferrin; Serine endopeptidases; Extracellular signal-regulated protein kinase; Hematology; iron homeostasis; Enzyme; Transferases; HFE; Homeostasis; Mitogen-activated protein kinase; Iron; Hemochromatosis gene; Peptidases; Signal transduction; Kinase; TfR2; Hydrolases; Furin; Hepcidin; Transferrin receptor 2
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2010.027003

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. 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. 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. 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.