Serum soluble transferrin receptor concentration is an accurate estimate of the mass of tissue receptors

R'Zik, Samir; Béguin, Yves

doi:10.1016/s0301-472x(01)00641-5

Cited by 68 publications

(48 citation statements)

References 28 publications

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“…Although the appearance of the soluble form of the transferrin receptor (sTfR) in human serum has been known for quite a long time (4) and its concentration is accepted as diagnostic marker for erythropoietic activity (5,6), little is known about the molecular basis of the shedding process, in particular the nature of the shedding protease involved. In diseases accompanied by enhanced erythropoiesis or TfR expression, like iron deficiency anemia, increased serum sTfR levels are observed (7)(8)(9)(10), whereas lower levels of serum sTfR were determined in patients with aplastic anemia (8).…”

Section: The Transferrin Receptor (Tfr)mentioning

confidence: 99%

Shedding of the Transferrin Receptor Is Mediated Constitutively by an Integral Membrane Metalloprotease Sensitive to Tumor Necrosis Factor α Protease Inhibitor-2

Kaup¹,

Dassler²,

Weise³

et al. 2002

Journal of Biological Chemistry

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The transferrin receptor (TfR) is a transmembrane protein that mediates cellular uptake of iron. Although the serum concentration of the soluble TfR (sTfR) is altered in several diseases and used for diagnostic purposes, the identity and regulation of the shedding protease is unknown. In this study we quantified sTfR release from microsomal membranes and leukocytic cell lines in the presence of numerous protease inhibitors and cell activating compounds. We show that sTfR release is mediated by an integral membrane metalloprotease and can be inhibited by matrix metalloproteinase inhibitor 2 and tumor necrosis factor ␣ protease inhibitor-2 (TAPI-2). Cleavage is also inhibited by a specific furin inhibitor, indicating that the protease is activated by a furin-like proprotein convertase. Whereas stimulation of the cells by the ectodomain shedding activator phorbol 12-N-myristate 13-acetate did not alter sTfR release significantly, the phosphatase inhibitor pervanadate led to an increase of TfR shedding in several leukocytic cell lines. Our results suggest that TfR shedding is constitutively mediated by a member of the metalloprotease family known as ADAM (for a disintegrin and metalloprotease).The transferrin receptor (TfR) 1 is a type II transmembrane protein that mediates uptake of iron by binding the iron carrier protein transferrin (Tf). Following internalization of the complex, iron is released in the acidic endosomes and the TfR⅐Tf complex recycles back to the cell surface where apotransferrin is released at neutral pH. The TfR is composed of two homologous peptide chains of 760 amino acids linked by two disulfide bonds (Cys-89 and Cys-98) close to the transmembrane domain. Each polypeptide is divided into a large C-terminal extracellular domain of 672 amino acids, a transmembrane domain of 21 amino acids, and an N-terminal cytoplasmic domain of 67 amino acids. The extracellular domain that binds Tf is kept by a juxtamembrane stalk at 2.9 nm from the plasma membrane (1). Within the stalk Thr-104 is O-glycosylated (2, 3), but detailed structure and function of the stalk remain unknown.Although the appearance of the soluble form of the transferrin receptor (sTfR) in human serum has been known for quite a long time (4) and its concentration is accepted as diagnostic marker for erythropoietic activity (5, 6), little is known about the molecular basis of the shedding process, in particular the nature of the shedding protease involved. In diseases accompanied by enhanced erythropoiesis or TfR expression, like iron deficiency anemia, increased serum sTfR levels are observed (7-10), whereas lower levels of serum sTfR were determined in patients with aplastic anemia (8). The sTfR level remains unchanged in anemia arising from chronic disease, so that it is a reliable marker to distinguish iron deficiency anemia from the anemia of chronic inflammation and liver disease (11). It was shown that a human red blood cell fraction does not have an own TfR-specific proteolytic activity, whereas a white blood cell fraction doe...

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Section: The Transferrin Receptor (Tfr)mentioning

confidence: 99%

Shedding of the Transferrin Receptor Is Mediated Constitutively by an Integral Membrane Metalloprotease Sensitive to Tumor Necrosis Factor α Protease Inhibitor-2

Kaup¹,

Dassler²,

Weise³

et al. 2002

Journal of Biological Chemistry

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“…Soluble TfR is produced by proteolysis, mediated by a membraneassociated serine protease that occurs mostly at the surface of exosomes within the multivesicular body prior to exocytosis [3]. The bulk of sTfR measured in serum is proportional to the mass of cellular TfR [4] and originates mostly from erythroblasts and to a lesser extent from reticulocytes [5].…”

Section: Introductionmentioning

confidence: 99%

Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

Béguin

2003

Clinica Chimica Acta

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398

316

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Iron transport in the plasma is carried out by transferrin, which donates iron to cells through its interaction with a specific membrane receptor, the transferrin receptor (TfR). A soluble form of the TfR (sTfR) has been identified in animal and human serum. Soluble TfR is a truncated monomer of tissue receptor, lacking its first 100 amino acids, which circulates in the form of a complex of transferrin and its receptor. The erythroblasts rather than reticulocytes are the main source of serum sTfR. Serum sTfR levels average 5.0 F 1.0 mg/l in normal subjects but the various commercial assays give disparate values because of the lack of an international standard. The most important determinant of sTfR levels appears to be marrow erythropoietic activity which can cause variations up to 8 times below and up to 20 times above average normal values. Soluble TfR levels are decreased in situations characterized by diminished erythropoietic activity, and are increased when erythropoiesis is stimulated by hemolysis or ineffective erythropoiesis. Measurements of sTfR are very helpful to investigate the pathophysiology of anemia, quantitatively evaluating the absolute rate of erythropoiesis and the adequacy of marrow proliferative capacity for any given degree of anemia, and to monitor the erythropoietic response to various forms of therapy, in particular allowing to predict response early when changes in hemoglobin are not yet apparent. Iron status also influences sTfR levels, which are considerably elevated in iron deficiency anemia but remain normal in the anemia of inflammation, and thus may be of considerable help in the differential diagnosis of microcytic anemia. This is particularly useful to identify concomitant iron deficiency in a patient with inflammation because ferritin values are then generally normal. Elevated sTfR levels are also the characteristic feature of functional iron deficiency, a situation defined by tissue iron deficiency despite adequate iron stores. The sTfR/ferritin ratio can thus describe iron availability over a wide range of iron stores. With the exception of chronic lymphocytic leukemia (CLL) and high-grade non-Hodgkin's lymphoma and possibly hepatocellular carcinoma, sTfR levels are not increased in patients with malignancies. We conclude that soluble TfR represents a valuable quantitative assay of marrow erythropoietic activity as well as a marker of tissue iron deficiency. D

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“…Circulating sTfR has been seen to increase with iron requirements or cellular growth. 27 and is reflective of the status of tissue iron stores. The sTfR is elevated under conditions of iron deficiency.…”

Section: Binned Datamentioning

confidence: 99%

Correlation Between Iron and alpha and pi Glutathione-S-Transferase Levels in Humans

Mauzy¹,

Johnson²,

Jacobsen³

et al. 2012

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Serum soluble transferrin receptor concentration is an accurate estimate of the mass of tissue receptors

Cited by 68 publications

References 28 publications

Shedding of the Transferrin Receptor Is Mediated Constitutively by an Integral Membrane Metalloprotease Sensitive to Tumor Necrosis Factor α Protease Inhibitor-2

Shedding of the Transferrin Receptor Is Mediated Constitutively by an Integral Membrane Metalloprotease Sensitive to Tumor Necrosis Factor α Protease Inhibitor-2

Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

Correlation Between Iron and alpha and pi Glutathione-S-Transferase Levels in Humans

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