Structure, Function and Clinical Significance of Transferrin Receptors

Abstract

Iron plays an essential role in a spectrum of metabolic processes. Cellular iron uptake is facilitated by transferrin receptor (TfR)-mediated endocytosis. In recent years more insight has been obtained in TfR physiology and the regulation of cellular iron homeostasis. The synthesis of TfR and the iron storage protein ferritin is regulated reciprocally at the post-transcriptional level according to the cellular iron status. As a result of externalization of TfR during the endocytic cycle, a soluble form of TfR can be detected in serum. The serum TfR (sTfR) level is closely related to erythroid TfR turnover and the prime determinants of the sTfR concentration are cellular iron demands and erythroid proliferation rate. In the absence of a hyperplastic erythropoiesis the sTfR level is a sensitive parameter of early tissue iron deficiency. The entire spectrum of body iron status can be assessed by measurement of serum ferritin and sTfR levels, with ferritin as marker of tissue iron stores and sTfR as index of tissue iron needs. The sTfR may be a promising tool to detect iron deficiency in inflammatory states and in the anaemia of chronic disease as its concentration is, in contrast to ferritin levels, not influenced by the acute phase response. Determination of sTfR levels may also improve assessment of body iron stores during pregnancy and in neonates. Finally, the sTfR may be a useful parameter to monitor erythropoiesis in various clinical settings, for instance in the prediction of the haematological response to erythropoietin treatment. However, standardization of the sTfR assay, with definition of reference and pathological ranges, is necessary for the definitive introduction of the sTfR as major parameter of iron metabolism.

Malarial anemia leads to adequately increased erythropoiesis in asymptomatic Kenyan children

“…14,15 Concentrations of sTfR measure both erythropoietic activity and the deficit in the erythron of iron; they are not influenced by the inflammatory response to infections. [16][17][18] Studies from Zaire, however, failed to show an effect on sTfR concentrations of malaria, 19,20 whereas reports from cross-sectional studies among nonhospitalized Africans give support to increased sTfR concentration in malaria. [21][22][23] Erythroid hyperplasia with dyserythropoiesis may also occur in malaria, and appears more common in patients with severe anemia and low-grade parasitemia than in those with acute malaria.…”

Enhancement of p53 gene transfer efficiency in hepatic tumor mediated by transferrin receptor through trans-arterial delivery

“…4,5 Transferrin receptor (TfR) is a transmembrane glycoprotein on the surface of cells and it serves as a ligand-receptor for transferrin (Tf ). [6][7][8] The human TfR is a homodimeric type II membrane protein consisting of two subunits covalently linked by intermolecular disulfide bonds. Each subunit has 760 amino acids, with a molecular weight of 90 kD.…”

“…9 TfR expression on the surface of cells may increase when cells are proliferating vigorously. 6 Tf is a single chain 80 kD glycoprotein consisting of 670-700 amino acids. Tf has two iron-binding sites which mediates the iron uptake into the cells through specific binding with Tf.…”

“…In malignant cells however, there are elevated levels of TfR expression attributed to a requirement of high iron level for their growth, and also higher TfR affinity to Tf is indicated. [5][6][7][8] Therefore, a complex of Tf as a ligand in conjunction with the therapeutic gene, or even with other drugs and proteins, transported by the Tf-TfR system, may be target-delivered and transferred into the malignant cells. 5,10 However, for some solid tumors such as hepatic cancers, local drug delivery via adjacent arteries of interventional therapy may be a much more effective sitedirected delivery system than systemic injection.…”

Immunological study of complex formation between soluble transferrin receptor and transferrin

“…Each TfR subunit binds one transferrin molecule (two transferrin molecules per one molecule of transferrin receptor) [5]. The complex of TfR and ironloaded Tf is transported into cells by means of internalization, where iron is released by pH-dependent mechanism (for details, see [6]). …”