Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2.
Hepcidin is a hormone secreted in response to iron loading and inflammation. Hepcidin binds to the iron exporter ferroportin, inducing its degradation and thus preventing iron entry into plasma. We determined that hepcidin binding to ferroportin leads to the binding and activation of the protein Janus Kinase2 (Jak2), which is required for phosphorylation of ferroportin. Ferroportin is a dimer and both monomers must be capable of binding hepcidin for Jak2 to bind to ferroportin. Once Jak2 is bound to the ferroportin dimer, both ferroportin monomers must be functionally competent to activate Jak2 and for ferroportin to be phosphorylated. These results show that cooperativity between the ferroportin monomers is required for hepcidin-mediated Jak2 activation and ferroportin down-regulation. These results provide a molecular explanation for the dominant inheritance of hepcidin resistant iron overload disease.
De Domenico
Ivana
I
Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132-2501, USA.
Lo
Eric
E
Ward
Diane M
DM
Kaplan
Jerry
J
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D064451:Hepcidins; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2