Transferrin Receptors in Erythropoiesis

Abstract

Erythropoiesis is a highly dynamic process giving rise to red blood cells from hematopoietic stem cells present in the bone marrow. Red blood cells transport oxygen to tissues thanks to the hemoglobin comprised of α- and β-globin chains and of iron-containing hemes. Erythropoiesis is the most iron-consuming process to support hemoglobin production. Iron delivery is mediated via transferrin internalization by the endocytosis of transferrin receptor type 1 (TFR1), one of the most abundant membrane proteins of erythroblasts. A second transferrin receptor—TFR2—associates with the erythropoietin receptor and has been implicated in the regulation of erythropoiesis. In erythroblasts, both transferrin receptors adopt peculiarities such as an erythroid-specific regulation of TFR1 and a trafficking pathway reliant on TFR2 for iron. This review reports both trafficking and signaling functions of these receptors and reassesses the debated role of TFR2 in erythropoiesis in the light of recent findings. Potential therapeutic uses targeting the transferrin-TFR1 axis or TFR2 in hematological disorders are also discussed.

Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents

“…Normal cells that express high levels of TfR1 may also be targeted by anti-TfR1 antibodies leading to unwanted toxicities. Cells that are of particular concern include hematopoietic committed progenitor cells expressing high levels of TfR1 such as erythroblasts, that require iron for heme synthesis (11,12,20,176). For most of the studies mentioned above using antibodies or antibody fragments targeting human TfR1, the xenograft mouse models used to determine anti-tumor efficacy are not useful for evaluating toxicity to normal cells due to the lack of cross-reactivity with mouse TfR1.…”

“…It is important to note that progenitor cells above are committed progenitor cells and are known to express high levels of TfR1 (11,12,20,176). However, pluripotent (non-committed) hematopoietic stem cells (HSC) express low to undetectable levels of TfR1 (176,184,185).…”

Iron and platelets: A subtle, under‐recognized relationship

“…If this is the case, it could open the possibility of a mechanism for iron delivery from the endosomes to the mitochondria either via a cytosolic pathway or, as proposed by Hamdi et al in reticulocytes, through direct interaction between endosomes and mitochondria (the “kiss‐and‐run” hypothesis) 42 . It should be asked whether TFR2 could also be involved in iron entry into platelets and its delivery to mitochondria 41 . The presence of non‐transferrin bound iron transporters 43 has not yet been confirmed.…”

“…42 It should be asked whether TFR2 could also be involved in iron entry into platelets and its delivery to mitochondria. 41 The presence of non-transferrin bound iron transporters 43 has not yet been confirmed.…”

“…Its expression was not found in human platelets by Hannuksela et al, 38 unlike the cellular iron sensor TFR2 or the HFE protein, 38,39 but it has been reported by the platelet proteome-data base. 40 It remains to be shown whether classical TFR1-iron endocytosis 41 is functional in platelets. If this is the case, it could open the possibility of a mechanism for iron delivery from the endosomes to the mitochondria either via a cytosolic pathway or, as proposed by Hamdi et al in reticulocytes, through direct interaction between endosomes and mitochondria (the "kiss-and-run" hypothesis).…”