Cell Metabolism
Volume 15, Issue 6, 6 June 2012, Pages 905-917
Journal home page for Cell Metabolism

Article
Molecular Mechanism of Hepcidin-Mediated Ferroportin Internalization Requires Ferroportin Lysines, Not Tyrosines or JAK-STAT

https://doi.org/10.1016/j.cmet.2012.03.017Get rights and content
Under an Elsevier user license
open archive

Summary

Ferroportin 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.

Highlights

► Ferroportin internalization does not require phosphorylation of tyrosines 302 or 303 ► Ferroportin internalization does not require JAK2 expression or activity ► Ferroportin internalization does not induce JAK-STAT signaling ► Ferroportin internalization is delayed by mutation of lysines 240 and 258

Cited by (0)