Molecular Mechanism of Hepcidin-Mediated Ferroportin Internalization Requires Ferroportin Lysines, Not Tyrosines or JAK-STAT
2012; Cell Press; Volume: 15; Issue: 6 Linguagem: Inglês
10.1016/j.cmet.2012.03.017
ISSN1932-7420
AutoresSandra L. Ross, Lynn Tran, Aaron Winters, Ki Jeong Lee, Cherylene A. Plewa, Ian N. Foltz, Chadwick King, Les P. Miranda, Jennifer R. Allen, Holger Beckman, Keegan S. Cooke, Gordon Moody, Barbra J. Sasu, Elizabeta Nemeth, Tomas Ganz, Graham Molineux, Tara Arvedson,
Tópico(s)Trace Elements in Health
ResumoFerroportin is the primary means of cellular iron efflux and a key component of iron metabolism. Hepcidin regulates Fpn activity by inducing its internalization and degradation. The mechanism of internalization is reported to require JAK2 activation, phosphorylation of Fpn tyrosine residues 302 and 303, and initiation of transcription through STAT3 phosphorylation. These findings suggest Fpn may be a target for therapeutic intervention through JAK2 modulation. To evaluate the proposed mechanism, Fpn internalization was assessed using several techniques combined with reagents that specifically recognized cell-surface Fpn. In vitro results demonstrated that Hepc-induced Fpn internalization did not require JAK2 or phosphorylation of Fpn residues 302 and 303, nor did it induce JAK-STAT signaling. In vivo, inhibition of JAK2 had no effect on Hepc-induced hypoferremia. However, internalization was delayed by mutation of two Fpn lysine residues that may be targets of ubiquitination.
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