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. 2015 May 20;22(15):1325–1336. doi: 10.1089/ars.2013.5819

FIG. 7.

FIG. 7.

Proposed model illustrating the relationship between HJV and HFE in regulating hepcidin expression in response to an acute increase in serum iron levels. Elevated serum iron triggers the phosphorylation of Smad1/5/8, which then binds to Smad4. The P-Smad1/5/8-Smad4 complex then translocates to the nucleus, where it drives the expression of hepcidin (via the Hamp1 gene). HFE and TFR2 can sense an increase serum iron and transduce a signal that, ultimately, leads to the phosphorylation of Smad1/5/8. Our results suggest that HJV predominantly controls the phosphorylation of Smad1/5/8, and HFE activity is dependent on HJV. In our mouse models of hereditary hemochromatosis (i.e., the Hfe−/−, Hjv−/−, and Hjv−/−Hfe−/− mice), HFE deletion partially reduces P-Smad1/5/8 levels and hepcidin expression on stimulation with holotransferrin; in contrast, deleting HJV blocks this pathway completely. Moreover, crosstalk between the Erk/MAPK and Bmp/Smad pathways was previously believed to be necessary for holotransferrin-induced hepcidin expression (dashed arrows).