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PubMed1992

The effect of different iron compounds on transferrin receptor expression in term human cytotrophoblast cells.

During pregnancy, the mother is faced with an increased food demand. A good example of this increased demand is iron (Fe). Fe is needed in all growing cells. During pregnancy, the Fe transport to the fetus increases enormously. This amount can easily induce an Fe deficiency in the mother. Fe supplementation is very important for her, but not for the Fe status of the fetus, which is protected against Fe toxicity as well as deficiency. The placenta seems to be autonomous in Fe uptake. Likely there is a regulation mechanism. The human placenta is hemomonochorial. The cell layer of the fetus in contact with the maternal blood is formed by syncytiotrophoblasts. Fe is transported to the placenta by transferrin. Transferrin binds to a transferrin receptor on the trophoblast membrane and is internalized via an endocytic pathway. During this cycle, Fe is released from transferrin and the transferrin-transferrin receptor complex is recycled to the membrane. Isolated trophoblast cells from term placentas form a syncytium in vitro, and transferrin receptors are expressed. Expression depends on the number of cells in culture, culture time, the amount of Fe available, and the Fe compound. By regulation of the number of transferrin receptors, trophoblasts are able to control their Fe uptake.

Binding Sites↗
PubMed2007

A structural comparison of human serum transferrin and human lactoferrin.

The transferrins are a family of proteins that bind free iron in the blood and bodily fluids. Serum transferrins function to deliver iron to cells via a receptor-mediated endocytotic process as well as to remove toxic free iron from the blood and to provide an anti-bacterial, low-iron environment. Lactoferrins (found in bodily secretions such as milk) are only known to have an anti-bacterial function, via their ability to tightly bind free iron even at low pH, and have no known transport function. Though these proteins keep the level of free iron low, pathogenic bacteria are able to thrive by obtaining iron from their host via expression of outer membrane proteins that can bind to and remove iron from host proteins, including both serum transferrin and lactoferrin. Furthermore, even though human serum transferrin and lactoferrin are quite similar in sequence and structure, and coordinate iron in the same manner, they differ in their affinities for iron as well as their receptor binding properties: the human transferrin receptor only binds serum transferrin, and two distinct bacterial transport systems are used to capture iron from serum transferrin and lactoferrin. Comparison of the recently solved crystal structure of iron-free human serum transferrin to that of human lactoferrin provides insight into these differences.

Amino Acid Sequence↗
PubMed1982

Transferrin receptors and iron uptake during erythroid cell development.

Experiments were performed to determine the level of transferrin receptors and rate of transferrin-bound iron uptake by various immature erythroid cell populations. Developing erythroid cells from the rat and mouse foetal liver at various stages of gestation were studied. In addition Friend leukaemic cells grown in culture were examined. The transferrin receptor level of Friend cells was similar to that of erythroid cells from the mouse foetal liver. During erythroid cell development the transferrin receptor level increased from about 300,000 per cell at the early normoblast stage to reach a maximum of about 8000,000 per cell on intermediate normoblasts. Further maturation of intermediate normoblasts was accompanied by a decline in the number of transferrin receptors, reaching a level of 105,000 in the circulating reticulocyte. The rate of iron uptake from transferrin during erythroid cell development was found to correlate closely with the number of transferrin receptors. In each of the immature erythroid cell populations studied the rate of iron uptake was about 36 iron atoms per receptor per hour. These results indicate that the level of transferrin receptors may be the major factor which determines the rate of iron uptake during erythroid cell development.

Aging↗
PubMed1989

Calcium chelators induce association with the detergent-insoluble cytoskeleton and functional inactivation of the transferrin receptor in reticulocytes.

Incubation of reticulocytes with EDTA, EGTA (ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid) and BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), but not with desferrioxamine B, at temperatures above 20 degrees C resulted in the loss of their ability to take up iron in a temperature-, time- and concentration-dependent manner. No inhibition of transferrin or iron uptake occurred if the incubations were performed at 20 degrees C or below. At higher temperatures, the inhibition was attributable to loss of functional transferrin receptors, not to altered affinity or endocytosis of the remaining receptors. The changes could not be reversed by washing the cells and reincubation in the presence of Ca2+, Mg2+ or Zn2+. However, they could be completely prevented by performing the initial incubation with chelators in the presence of diferric transferrin and partly prevented by the use of apotransferrin. Incubation with the chelators resulted in much less reduction in the ability of the cells to bind anti-transferrin receptor immunoglobulin than transferrin. The fate of the receptor was studied by polyacrylamide gel electrophoresis of reticulocyte membrane proteins before and after extraction with Triton X-100, and by immunological staining of Western blots for the transferrin receptor. Treatment of the cells with EDTA led to a loss of the ability of Triton X-100 to solubilize the receptor and its retention in the Triton-insoluble cytoskeletal matrix of the cells. It is concluded that incubation of reticulocytes with the chelators at temperatures above 20 degrees C causes an altered interaction of the transferrin receptor with the cytoskeleton. This change, which is probably due to chelation of Ca2+ in the cell membrane, is accompanied by an irreversible loss of the receptor's ability to bind transferrin.

Animals↗
PubMed1991

A 41 kDa transferrin related molecule acts as an autocrine growth factor for HL-60 cells.

HL-60 cells produce an autostimulatory growth factor. Since the stimulatory effect of HL-60 conditioned medium is only observed in the absence of exogenous transferrin we have assayed HL-60 cells for the production of transferrin and found that they produce polypeptides which react with transferrin antibodies. 35S-methionine labelling, immunoprecipitation and subsequent separation by SDS-gel electrophoresis reveals the presence of a major transferrin related 41 +/- 2 kDa species released by HL-60 cells. Physiological levels of iron salts completely abolish the requirement of exogenous transferrin which indicates that the endogenous transferrin related polypeptides in the presence of exogenous inorganic iron salts are sufficient for the proliferation of HL-60 cells provided insulin or related growth factors are present. The addition of transferrin receptor antibodies inhibits the stimulatory action of the endogenous transferrin related activity.

Cell Division↗
PubMed1992

The role of transferrin in heme transport.

Porphyrin accumulation by proliferating cells, e.g., those associated with cancers or wounds, tends to correlate with increased transferrin receptor density. To determine whether transferrin might be implicated in porphyrin transport, fluorescence and absorption spectroscopy were used to study the interaction of porphyrins with transferrin. A single high-affinity binding site for heme and other porphyrins (Kd approximately 20-25 nM) was detected by fluorescence spectroscopy. Difference spectroscopy revealed three additional heme-binding sites. These sites were distinct from the iron-binding sites: 1) Apotransferrin and diferric transferrin bound porphyrins with equal affinity; 2) 59Fe was not displaced from transferrin by porphyrins. Murine erythroleukemia cells incubated with [59Fe]hemin-[125I]transferrin internalized both labels concomitantly. Accumulation of [59Fe]hemin could be blocked by a 100-fold excess of diferric transferrin but not by apotransferrin. These results indicate that cells can internalize exogenous heme, and possibly porphyrins, bound to transferrin via its receptor.

Animals↗
PubMed1985

Uptake of sialo and asialo transferrins by isolated rat hepatocytes. Comparison of a heterologous and a homologous system.

Incubation of isolated rat hepatocytes with different human sialo transferrins shows that interaction with the specific transferrin receptor is insensitive to differences in the carbohydrate composition of the glycans. Asialo transferrins lead to an increased iron uptake, which is dependent on the amount of exposed galactose. This is explained by the presence of the asialo glycoprotein (AsGP) receptor. Experiments with selective saturation of the two receptor systems show that on incubation with human asialo transferrin (AsHTf) transferrin uptake proceeds increasingly via the AsGP receptor on raising the concentration. Homologous rat asialo transferrin (AsRTf) behaves similarly, but less pronounced. Iron is accumulated via both receptor systems in the heterologous system, but only via the transferrin receptors in the homologous system. The difference in interaction with the AsGP-receptor may be caused by the difference in galactose content of the two asialo transferrins. As an explanation for the differences in intracellular metabolism a hitherto unknown recognition system for species specificity is postulated which protects homologous AsRTf from degradation, but directs foreign AsTf to lysosomes.

Animals↗
PubMed1983

Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor.

The fate of the transferrin receptor during in vitro maturation of sheep reticulocytes has been followed using FITC- and 125I-labeled anti-transferrin-receptor antibodies. Vesicles containing peptides that comigrate with the transferrin receptor on polyacrylamide gels are released during incubation of sheep reticulocytes, tagged with anti-transferrin-receptor antibodies. Vesicle formation does not require the presence of the anti-transferrin-receptor antibodies. Using 125I-surface-labeled reticulocytes, it can be shown that the 125I-labeled material which is released is retained by an immunoaffinity column of the anti-transferrin-receptor antibody. Using reticulocytes tagged with 125I-labeled anti-transferrin-receptor antibodies to follow the formation of vesicles, it can be shown that at 0 degree C or in phosphate-buffered saline the rate of vesicle release is less than that at 37 degrees C in culture medium. There is selective externalization of the antibody-receptor complex since few other membrane proteins are found in the externalized vesicles. The anti-transferrin-receptor antibodies cause redistribution of the receptor into patches that do not appear to be required for vesicle formation.

Animals↗
PubMed1991

NADH oxidase of liver plasma membrane stimulated by diferric transferrin and neoplastic transformation induced by the carcinogen 2-acetylaminofluorene.

NADH oxidase of purified plasma membranes (electron transfer from NADH to oxygen) was stimulated by the growth factor diferric transferrin. This stimulation was of an activity not inhibited by cyanide and was not seen in plasma membranes prepared from hyperplastic nodules from liver of animals fed the hepatocarcinogen, 2-acetylaminofluorene, nor was it due to reduction of iron associated with diferric transferrin. With plasma membranes from nodules, the activity was already elevated and the added transferrin was without effect. The stimulation by diferric transferrin did not correlate with the absence of transferrin receptors which were increased at the nodule plasma membranes. With liver plasma membranes, the stimulation by diferric transferrin raised the plasma membrane NADH oxidase specific activity to approximately that of the nodule plasma membranes. In contrast to NADH oxidase, which was markedly stimulated by the diferric transferrin, NADH ferricyanide oxidoreductase or reduction of ferric ammonium citrate by liver plasma membranes was approximately equal to or slightly greater than that of the nodule plasma membrane and unaffected by diferric transferrin. The results suggest the possibility of coupling of NADH oxidase activity to a growth factor response in mammalian cells as observed previously for this enzyme in another system.

2-Acetylaminofluorene↗
PubMed1986

Transplasmalemma electron transport from cells is part of a diferric transferrin reductase system.

Intact cells are known to reduce external, impermeable electron acceptors. We now show that cells can reduce the iron in diferric transferrin at the cell surface and that this reduction reaction depends on the transferrin receptor as well as the transmembrane electron transport system. Reduction of external diferric transferrin is accompanied by oxidation of internal NADH which indicates that the transmembrane enzyme is an NADH diferric transferrin reductase. Highly purified liver plasma membranes have NADH diferric transferrin reductase activity which shows properties similar to the diferric transferrin reductases activity of intact cells. Cell growth stimulation by diferric transferrin and other impermeable oxidants which can react with the diferric transferrin reductase can be based on electron transport through he plasma membrane.

Cell Membrane↗
PubMed1999

Iron-independent neuronal expression of transferrin receptor mRNA in the rat.

Neuronal transferrin receptor protein expression is highly upregulated widely in CNS following iron deficiency. Using the medial habenular nucleus as a model of neuronal transferrin receptor mRNA expression, the present study examined 17-day-old rats subjected to variations in dietary iron. Changing the iron availability resulted in alterations in plasma and cerebrospinal fluid (CSF) levels of transferrin and iron. The iron-binding capacity of transferrin in CSF was exceeded in normal and iron-overloaded rats. In spite of a lowering of the concentration of brain iron by approximately 22% in iron-deficient rats, neuronal transferrin receptor mRNA was not affected when measured by quantitative densitometry. Brain iron and neuronal transferrin receptor mRNA expression was unaltered in iron overloaded rats. The absence of a rise in transferrin receptor mRNA during iron deficiency suggests that neuronal transferrin receptor mRNA expression is regulated by another mechanism than the post-transcriptional regulation mechanism, which has been attributed to cells of non-neural tissue.

Animals↗
PubMed1984

Epidermal growth factor rapidly induces a redistribution of transferrin receptor pools in human fibroblasts.

Treatment of human fibroblasts with epidermal growth factor (EGF) results in a rapid increase (less than 5 min) in the ability of the cells to bind 125I-labeled transferrin to surface receptors. Scatchard analyses of EGF-treated cells indicate that this increase was due to an increase in the number of transferrin receptors at the cell surface rather than to alterations in ligand-receptor affinity. The EGF-induced increase in transferrin receptors was transient, reaching a peak by 5 min and then declining back to near basal levels by 45 min. Increases in transferrin receptor number were observed when approximately equal to 1% of the EGF receptors were occupied and were maximal at 16% occupancy. EGF treatment accelerated the rate at which previously internalized 125I-labeled transferrin-receptor complexes were returned to the cell surface. The kinetics and magnitude of the loss of intracellular transferrin receptors was sufficient to account for the increase in surface transferrin receptors. We conclude from these studies that one of the earliest effects of EGF treatment is the induced translocation of an intracellular compartment to the cell surface. This intracellular compartment contains transferrin receptors and may be part of the pathway involved in the normal recycling of cell surface proteins.

Cells, Cultured↗
PubMed1992

Selective stimulation of prostatic carcinoma cell proliferation by transferrin.

Aggressive prostatic carcinomas most frequently metastasize to the skeletal system. We have previously shown that cultured human prostatic carcinoma cells are highly responsive to growth factors found in human bone marrow. To identify the factor(s) responsible for the increased prostatic carcinoma cell proliferation, we fractionated crude bone marrow preparations by using hydroxylapatite HPLC. The major activity peak contained two high molecular weight bands (M(r) = 80,000 and 69,000) that cross-reacted with antibodies to human transferrin and serum albumin, respectively. Bone marrow transferrin, purified to apparent homogeneity by using DEAE-Affi-Gel Blue chromatography, anti-transferrin affinity chromatography, and hydroxylapatite HPLC, markedly stimulated prostatic carcinoma cell proliferation, whereas human serum albumin showed no significant growth factor activity. Marrow preparations, depleted of transferrin by passage over an anti-transferrin affinity column, lost greater than 90% of their proliferative activity. In contrast to the response observed with the prostatic carcinoma cell lines, a variety of human malignant cell lines, derived from other primary sites and metastatic to sites other than bone marrow, showed a reduced response to purified marrow-derived transferrin. These results suggest that rapid growth of human prostatic carcinoma metastases in spinal bone may result from a combination of conditions that include (i) drainage of prostatic carcinoma cells into the paravertebral circulation, (ii) high concentrations of available transferrin in bone marrow, and (iii) increased sensitivity of prostatic carcinoma cells to the mitogenic activity of transferrin.

Bone Marrow↗
PubMed1991

Apical and basolateral transferrin receptors in polarized BeWo cells recycle through separate endosomes.

Contrary to most other epithelia, trophoblasts in the human placenta, which form the physical barrier between the fetal and the maternal blood circulation, express high numbers of transferrin receptors on their apical cell surface. This study describes the establishment of a polarized trophoblast-like cell line BeWo, which exhibit a high expression of transferrin receptors on the apex of the cells. Cultured on permeable filter supports, BeWo cells formed a polarized monolayer with microvilli on their apical cell surface. Across the monolayer a transepithelial resistance developed of approximately 600 omega.cm2 within 4 d. Depletion of Ca2+ from the medium decreased the resistance to background levels, showing its dependence on the integrity of tight junctions. Within the same period of time the secretion of proteins became polarized. In addition, the compositions of integral membrane proteins at the apical and basolateral plasma membrane domains were distinct as determined by domain-selective iodination. Similar to placental trophoblasts, binding of 125I-labeled transferrin to BeWo monolayers revealed that the transferrin receptor was expressed at both plasma membrane domains. Apical and basolateral transferrin receptors were found in a 1:2 surface ratio and exhibited identical dissociation constants and molecular weights. After uptake, transferrin recycled predominantly to the domain of administration, indicating separate recycling pathways from the apical and basolateral domain. This was confirmed by using diaminobenzidine cytochemistry, a technique by which colocalization of endocytosed 125I-labeled and HRP-conjugated transferrin can be monitored. No mixing of the two types of ligands was observed, when both ligands were simultaneously internalized for 10 or 60 min from opposite domains, demonstrating that BeWo cells possess separate populations of apical and basolateral early endosomes. In conclusion, the trophoblast-like BeWo cell line can serve as a unique model to compare the apical and basolateral endocytic pathways of a single ligand, transferrin, in polarized epithelial cells.

Cell Line↗
PubMed1993

The End2 mutation in CHO cells slows the exit of transferrin receptors from the recycling compartment but bulk membrane recycling is unaffected.

We have characterized a new CHO cell line (12-4) derived from a parental line, TRVb-1, that expresses the human transferrin receptor. This mutant belongs to the end2 complementation group of endocytosis mutants. Like other end2 mutants, the endosomes in 12-4 cells show a partial acidification defect. These cells internalize LDL and transferrin at 70% of the rate of parental cells and externalize transferrin at 55% of the parental rate (Johnson, L. S., J. F. Presley, J. C. Park, and T. E. McGraw. J. Cell Physiol. 1993). In this report, we have used fluorescence microscopy to determine which step in receptor trafficking is affected in the mutants. Transferrin is sorted from LDL and is delivered to a peri-centriolar recycling compartment at rates similar to parental cells. However, the rate constant for exit of transferrin from the recycling compartment in mutant cells is 0.025 min-1 vs 0.062 min-1 in the parental line. We also measured the trafficking of a bulk membrane marker, 6-[N-[7-nitrobenzo-2-oxa-1,3-diazol-4-yl]-amino]hexanoyl- sphingosylphosphorylcholine (C6-NBD-SM) that labels the exofacial side of the plasma membrane. C6-NBD-SM enters the same recycling compartment as transferrin, and it exits the recycling compartment at a rate of 0.060-0.065 min-1 in both parental and 12-4 cells. We conclude that bulk membrane flow in the recycling pathway of 12-4 cells is normal, but exit of transferrin from the recycling compartment is slowed due to retention in this compartment. Thus, in the mutant cell line the recycling compartment carries out a sorting function, retaining transferrin over bulk membrane.

4-Chloro-7-nitrobenzofurazan↗
PubMed1984

Receptor-mediated endocytosis of alpha 2-macroglobulin and transferrin in rat caput epididymal epithelial cells in vitro.

The endocytic activity of epithelial cells from the rat epididymis in vitro has been examined by following the uptake of tracer compounds conjugated to proteins. Transferrin-gold and alpha 2-macroglobulin-gold were taken up initially in coated pits, internalized and sequestered into tubular-vesicular structures, multivesicular bodies and, in the case of alpha 2-macroglobulin, into lysosomes. Uptake could be prevented by an excess of unlabeled protein. Studies using 125I-alpha 2-macroglobulin and 125I-transferrin also showed that the uptake of these proteins was specific and could be displaced with increasing amounts of unlabeled protein. In addition, binding of 125I-transferrin to cells was saturable at 4 degrees C. These studies indicate that transferrin and alpha 2-macroglobulin are taken up by receptor-mediated endocytosis. In contrast, a fluid phase marker, bovine serum albumin-gold (BSA-gold), was initially taken up predominantly in uncoated caveolae rather than coated pits, and could not be displaced with excess BSA. By virtue of their charge, polycationized ferritin and unlabeled colloidal gold were taken up and internalized by adsorptive endocytosis, a pathway which is similar to fluid phase endocytosis. The uptake and internalization of alpha 2-macroglobulin and transferrin differed in a number of respects. Uptake and internalization of alpha 2-macroglobulin but not of transferrin was dependent on extracellular calcium. Only alpha 2-macroglobulin was transferred into lysosomes, whereas transferrin was recycled to the cell surface. Although the proton ionophore, monensin, and the transglutaminase inhibitor, dansylcadaverine, did not stop uptake and internalization of either alpha 2-macroglobulin or transferrin, they did prevent the transfer of alpha 2-macroglobulin to lysosomes.

Adsorption↗
PubMed1986

Receptor-mediated endocytosis of transferrin by Sertoli cells of the rat.

Binding of 125I-transferrin (125I-Tf) to the plasma membrane of Sertoli cells and its endocytosis were analyzed by means of light- and electron-microscope quantitative radioautography. Five minutes after 125I-Tf was injected into the interstitial space of the testis, a strong labeling of the basal aspect of the seminiferous epithelium was observed in light-microscope radioautographs. Injection of the same dose of 125I-Tf plus a 200-fold excess of cold transferrin resulted in a marked diminution of the radioautographic reaction, indicating that the initial strong labeling with radiolabeled transferrin was specific. These results were consistent with the localization of immunoreactive fluorescence of transferrin receptor at the base of the seminiferous epithelium. In electron-microscope radioautographs of tubules collected at 5 min after injection, the membrane of Sertoli cells facing the basement membrane was well labeled with 125I-Tf. At 15 and 30 min, the plasma membrane was less intensely labeled, but the silver grains were then seen overlying multivesicular bodies with an electron-lucent matrix, identified as endosomes. This population of endosomes was always seen at a short distance from the basal membrane of Sertoli cells. At 90 min, no more labeling of the plasma membrane, endosomes, or any other cytoplasmic component was observed. Isolated seminiferous tubules and Sertoli cells labeled with 125I-Tf at 4 degrees C were rinsed and reincubated in a label-free medium at 37 degrees C for various periods of time from 5 to 90 min. A radioactive protein precipitated by trichloroacetic acid, presumably intact transferrin, was released from the tubules into the incubating medium; when measured, it was found to increase rapidly from 5 to 45 min and stabilize thereafter. These results suggest that transferrin was internalized by receptor-mediated endocytosis, reached endosomes, and then was released to the extratubular space. When native ferritin (NF), a tracer for fluid-phase endocytosis, was infused within the lumen of seminiferous tubules and 125I-Tf was simultaneously injected into the interstitial space, both markers rapidly reached different populations of endosomes. Endosomes labeled with NF, scattered throughout the cytoplasm, evolved with time into dense multivesicular bodies and secondary lysosomes, whereas radiolabeled transferrin reached only the endosomes located in the basal cytoplasm of Sertoli cells. The latter thus appeared to be principally involved in the uptake and recycling of transferrin.

Animals↗
PubMed1988

Inability to detect transferrin receptors on P. falciparum parasitized red cells.

The mechanism by which P. falciparum takes up iron from transferrin has been explored. Binding of 125I labelled transferrin to parasitized red cells at 37 degrees C is two-fold greater than to control cells; at 0 degrees C there is no significant difference. The binding is non-specific as judged from the following: it is not saturable; it is not limited to transferrin as lactoferrin (which has iron binding domains) and bovine serum albumin (which does not) also bind in excess to parasitized red cells. A transferrin receptor complex could not be demonstrated when parasitized red cells, to which 125I transferrin was bound, were solubilized in Triton X100. Previous observation showed that uptake of transferrin iron by parasitized red cells is not accompanied by equimolar uptake of transferrin protein. We therefore suggest that nonspecifically bound transferrin is endocytosed, that the protein is degraded and the iron selectively retained.

Animals↗