Transferrin receptor 2 (TFR2), a
protein homologous to the cell
iron importer TFR1, is expressed in the liver and erythroid cells and is reported to bind
diferric transferrin, although at lower affinity than TFR1. TFR2 gene is mutated in
type 3 hemochromatosis, a disorder characterized by
iron overload and inability to upregulate
hepcidin in response to
iron. Liver TFR2 is considered a sensor of
diferric transferrin, possibly in a complex with
hemochromatosis protein. In erythroid cells TFR2 is a partner of
erythropoietin receptor (EPOR) and stabilizes the receptor on the cell surface. However, Tfr2 null mice as well as TFR2
hemochromatosis patients do not show defective erythropoiesis and tolerate repeated phlebotomy. The
iron deficient Tfr2-Tmprss6 double knock out mice have higher red cells count and more severe microcytosis than the liver-specific Tfr2 and Tmprss6 double knock out mice. TFR2 in the bone marrow might be a sensor of
iron deficiency that protects against excessive microcytosis in a way that involves EPOR, although the mechanisms remain to be worked out.