Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2

Proceedings of the National Academy of Sciences of the United States of America - Tập 106 Số 10 - Trang 3800-3805 - 2009
Ivana De Domenico1,2, Eric Lo2,3, Diane McVey Ward2,4, Jerry Kaplan2,4
1Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132-2501, USA
2Departments of aPathology and
3University of Utah
4MICROBIOLOGY & IMMUNOLOGY

Tóm tắt

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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 106 Số 10

3800-3805

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