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PubMed1986

Micropuncture studies of receptor-mediated endocytosis of transferrin in the rat epididymis.

The concentration of transferrin in fluids collected by micropuncture techniques from the rete testis and zones 1A, 2, 5A, and 6B of the rat ductus epididymidis was 44, 527, 113, and 49 ng/microliter, respectively. When changes in fluid volume were taken into account, it was found that transferrin was concentrated by the efferent ducts, whereas the amount of endogenous luminal transferrin declined from the caput to the cauda epididymidis. Using transferrin-gold as an electron dense marker, we showed that the decline in the concentration of transferrin along the epididymis could be attributed to its cumulative receptor-mediated endocytosis by the lining principal cells. No significant difference in the net receptor-mediated endocytosis of transferrin-gold was found between the proximal caput and corpus epididymidis in vivo.

Animals↗
PubMed2004

Transferrin is required for early T-cell differentiation.

Transferrin, the major plasma iron carrier, mediates iron entry into cells through interaction with its receptor. Several in vitro studies have demonstrated that transferrin plays an essential role in lymphocyte division, a role attributed to its iron transport function. In the present study we used hypotransferrinaemic (Trf(hpx/hpx)) mice to investigate the possible involvement of transferrin in T lymphocyte differentiation in vivo. The absolute number of thymocytes was substantially reduced in Trf(hpx/hpx) mice, a result that could not be attributed to increased apoptosis. Moreover, the proportions of the four major thymic subpopulations were maintained and the percentage of dividing cells was not reduced. A leaky block in the differentiation of CD4(-) CD8(-) CD3(-) CD44(-) CD25(+) (TN3) into CD4(-) CD8(-) CD3(-) CD44(-) CD25(-) (TN4) cells was observed. In addition, a similar impairment of early thymocyte differentiation was observed in mice with reduced levels of transferrin receptor. The present study demonstrates, for the first time, that transferrin itself or a pathway triggered by the interaction of transferrin with its receptor is essential for normal early T-cell differentiation in vivo.

Animals↗
PubMed1991

The influence of transferrin binding to L2C guinea pig leukemic lymphocytes on the endocytosis cycle kinetics of its receptor.

The parameters regulating the internalization and recycling of transferrin-specific receptors were determined in guinea pig leukemic B lymphocytes, in the absence or presence of ligand. We show that after the cells were purified, 45-56% of the total receptors were on the cell surface. In the absence of transferrin, unoccupied receptors are quickly internalized (rate constant, 0.12 min-1) whereas their recycling is much slower (rate constant, 0.026 min-1). This difference between endocytosis and recycling rates leads to a balanced receptor distribution with only 22% of the total receptors outside after incubation of the cells for 20-30 min at 37 degrees C. The internalization rate of occupied receptors, measured in the presence of transferrin is faster (rate constant, 0.21 min-1) than that of unoccupied receptors calculated in the absence of transferrin (0.12 min-1; see above). On the other hand, mere binding of transferrin to its receptor, without internalization, arrested by cytoplasm acidification, is sufficient to induce a large increase (by a factor of seven) in the recycling rate of unoccupied internal receptors from 0.026 min-1 to 0.17 min-1. Thus, in these lymphocytes, transferrin mobilizes internal receptors by modifying the kinetic rates of internalization and recycling, leading to a new equilibrium between external and internal receptors.

Animals↗
PubMed2002

Growth of Neisseria gonorrhoeae in the female mouse genital tract does not require the gonococcal transferrin or hemoglobin receptors and may be enhanced by commensal lactobacilli.

Neisseria gonorrhoeae is capable of utilizing a variety of iron sources in vitro, including human transferrin, human lactoferrin, hemoglobin, hemoglobin-haptoglobin complexes, heme, and heterologous siderophores. Transferrin has been implicated as a critical iron store for N. gonorrhoeae in the human male urethra. The demonstration that gonococci can infect the lower genital tracts of estradiol-treated BALB/c mice in the absence of human transferrin, however, suggests that other usable iron sources are present in the murine genital tract. Here we demonstrate that gonococcal transferrin and hemoglobin receptor mutants are not attenuated in mice, thereby ruling out transferrin and hemoglobin as essential for murine infection. An increased frequency of phase variants with the hemoglobin receptor "on" (Hg(+)) occurred in ca. 50% of infected mice; this increase was temporally associated with an influx of neutrophils and detectable levels of hemoglobin in the vagina, suggesting that the presence of hemoglobin in inflammatory exudates selects for Hg(+) phase variants during infection. We also demonstrate that commensal lactobacilli support the growth of N. gonorrhoeae in vitro unless an iron chelator is added to the medium. We hypothesize that commensal lactobacilli may enhance growth of gonococci in vivo by promoting the solubilization of iron on mucosal surfaces through the production of metabolic intermediates. Finally, transferrin-binding lipoprotein (TbpB) was detected on gonococci in vaginal smears, suggesting that although gonococci replicate within the genital tracts of mice, they may be sufficiently iron-stressed to express iron-repressible proteins. In summary, these studies support the potential role of nontransferrin, nonhemoglobin iron sources during gonococcal infection of the female genital tract.

Amino Acid Sequence↗
PubMed2002

Regulation of transferrin-induced endocytosis by wild-type and C282Y-mutant HFE in transfected HeLa cells.

The hereditary hemochromatosis protein HFE is known to complex with the transferrin receptor; however, its function regarding endocytosis of transferrin is unclear. We performed patch-clamp capacitance measurements in transfected HeLa cells carrying wild-type or C282Y-mutant HFE cDNA under the control of a tetracycline-sensitive promoter. Whole cell experiments in cells with suppressed expression of wild-type HFE revealed a decrease in membrane capacitance, reflecting predominance of endocytosis in the presence of transferrin. Cells overexpressing C282Y-mutant HFE displayed less intense capacitance decreases, whereas no significant decrease was observed in cells overexpressing wild-type HFE. The formation of single endocytic vesicles in cells with suppressed expression of wild-type HFE was greatly increased in the presence of transferrin as revealed by cell-attached recordings. According to their calculated diameters, many of these vesicles corresponded to clathrin-coated vesicles. These results suggest that wild-type HFE negatively modulates the endocytic uptake of transferrin. This inhibitory effect is attenuated in cells expressing C282Y-mutant HFE. Time-resolved measurements of cell membrane capacitance provide a powerful tool to study transferrin-induced endocytosis in single cells.

Electric Capacitance↗
PubMed2000

Gene expression of divalent metal transporter 1 and transferrin receptor in duodenum of Belgrade rats.

Regulation of iron absorption is thought to be mediated by the amount of iron taken up by duodenal crypt cells via the transferrin receptor (TfR)-transferrin cycle and the activity of the divalent metal transporter (DMT1), although DMT1 cannot be detected morphologically in crypt cells. We investigated the uptake of transferrin-bound iron by duodenal enterocytes in Wistar rats fed different levels of iron and Belgrade (b/b) rats in which iron uptake by the transferrin cycle is defective because of a mutation in DMT1. We showed that DMT1 in our colony of b/b rats contains the G185R mutation, which in enterocytes results in reduced cellular iron content and increased DMT1 gene expression similar to levels in iron deficiency of normal rats. In all groups the uptake of transferrin-bound iron by crypt cells was directly proportional to plasma iron concentration, being highest in iron-loaded Wistar rats and b/b rats. We conclude that the uptake of transferrin-bound iron by developing enterocytes is largely independent of DMT1.

Animals↗
PubMed1988

In vivo transferrin-iron receptor relationships in erythron of rats.

Quantitative measurements of transferrin receptors, tissue transferrin, tissue iron uptake, and erythroid cellularity have been carried out in rats with altered erythropoiesis and altered iron balance. Erythroid receptors increased with erythroid hyperplasia, with the increase in proportion to the increased number of red cell precursors in phenylhydrazine-treated rats. Receptors increased disproportionately in iron deficiency due to both erythroid hyperplasia and an increase in receptors in the individual cell. There was a ratio of 1:1 between cell-related transferrin and receptors in circulating reticulocytes but a disproportionate amount of cell-related transferrin in fixed erythroid tissues (marrow and spleen), suggesting that there was some other reason for the concentration of transferrin in these tissues. Erythron iron uptake was increased in proportion to the increased receptor number in phenylhydrazine-treated animals but was reduced in iron deficiency because of the limited amount of iron-bearing transferrin. These studies demonstrate the dominant role of erythron cellularity and iron status in vivo in determining total receptor number and the importance of receptor number and iron supply in tissue iron uptake.

Anemia, Hemolytic↗
PubMed1996

Mobilferrin is an intermediate in iron transport between transferrin and hemoglobin in K562 cells.

Iron is bound to transferrin in the plasma. A specific receptor on the cell surface binds transferrin and internalizes transferrin and the iron in clathrin-coated pits. These invaginate to form vesicles which release iron to the cytoplasm. Inorganic iron can be transported by an alternative pathway from iron citrate, utilizing a cell surface integrin and a cytoplasmic protein mobilferrin. This article shows that the two pathways donate iron to mobilferrin which acts as an intermediate between the iron bound to transferrin and the incorporation of iron into hemoglobin. Mobilferrin is found associated with the transferrin containing vesicles, and becomes labeled with iron released from transferrin in the vesicles. Mobilferrin is also found in the cytoplasm where pulse-chase experiments show that it, in turn, releases iron to be used for the synthesis of hemoglobin.

Biological Transport, Active↗
PubMed1996

An immunohistochemical localization of transferrin binding protein in the chicken respiratory tract.

Transferrin binding protein (TfBP), a glycoprotein, is originally purified from the chicken oviduct. Recently, TfBP has been revealed as a novel transferrin binding protein, structurally related to the chicken heat shock protein 108. The physiological function of this protein, however, has not yet been established. Antiserum to TfBP was found to stain selectively transferrin- and iron-rich oligodendrocytes of the normal chicken brain, suggesting a role for this protein in connection with transferrin and iron storage in these cells. In this study, we further demonstrate a TfBP-immunoreactivity in the chicken respiratory tract mucosa, where transferrin is known to be present and have antioxidant and antibacterial properties. A strong TfBP immunoreactivity was revealed in certain regions of the respiratory tract. In the trachea and bronchi, TfBP-immunoreactive product was localized specifically to the mucous gland cells, whereas ciliated epithelial cells were negative. In the lung, TfBP immunoreactivity was mostly confined to the parabronchi and atria. The immunoreactive products were found in the cytoplasm of the epithelial cells lining the parabronchial and atrial walls. These findings suggest that the presence of TfBP in the airway mucosa may be a necessary condition for transferrin concentration in the extracellular milieu of the respiratory tract.

Animals↗
PubMed1991

Transferrin-adriamycin conjugates which inhibit tumor cell proliferation without interaction with DNA inhibit plasma membrane oxidoreductase and proton release in K562 cells.

Conjugates of adriamycin crosslinked to transferrin with glutaraldehyde inhibit proliferation of transformed cells. Conjugates of this type inhibit oxidoreductase activity in the plasma membrane of K562 cells, and the inhibition of electron transport is found at concentrations ten times lower than concentrations of free adriamycin which inhibit electron transport and cell growth. The transferrin-adriamycin conjugate inhibits ferricyanide reduction, diferric transferrin reduction and plasma membrane NADH oxidase activity stimulated by transferrin. Activation of proton release from the K562 cells by diferric transferrin also is inhibited by the conjugate, and conjugate kills cells more effectively than free adriamycin. Since the conjugate does not transfer adriamycin to the nucleus, the growth control may be based on inhibition of the transferrin regulated redox system and Na+/H+ antiport activity at the plasma membrane.

Carrier Proteins↗
PubMedDate not supplied

[Localization of the site of human transferrin interacting with cellular receptors using monoclonal antibodies].

Antigenic determinants of the human transferrin molecule on the sublobe and lobe levels were localized for 7 monoclonal antibodies. Antibodies used have different effects on the interaction of the transferrin with its receptor. It was concluded that transferrin-receptor recognition was determined by NH2-lobe, the N2-sublobe playing major part. Dimerization of the transferrin molecules in solution was detected. Using the panel of monoclonal antibodies it was shown that dimerization accomplished by means of the COOH-lobes of transferrin molecules, the sites of interaction of the NH2-lobe with receptor being exposed. A model of the transferrin - receptor complex is proposed.

Antibodies, Monoclonal↗
PubMed1990

Hemopexin-dependent down-regulation of expression of the human transferrin receptor.

To investigate the regulation mechanism of the uptake of iron and heme iron by the cells and intracellular utilization of iron, we examined the interaction between iron uptake from transferrin and hemopexin-mediated uptake of heme by human leukemic U937 cells or HeLa cells. U937 cells exhibited about 40,000 hemopexin receptors/cell with a dissociation constant (Kd) of 1 nM. Heme bound in hemopexin was taken up by U937 cells or HeLa cells in a receptor-mediated manner. Treatment of both species of cells with hemopexin led to a rapid decrease in iron uptake from transferrin in a hemopexin dose-dependent manner, and the decrease seen in case of treatment with hemin was less than that seen with hemopexin. The decrease of iron uptake by hemopexin contributed to a decrease in cell surface transferrin receptors on hemopexin-treated cells. Immunoblot analysis of the transferrin receptors revealed that the cellular level of receptors in U937 cells did not vary during an 8-h incubation with hemopexin although the number of surface receptors as well as iron uptake decreased within the 2-h incubation. After 4 h of incubation of the cells with hemopexin, a decrease of the synthesis of the receptors occurred. Thus, the down-regulation of transferrin receptors by hemopexin can be attributed to at least two mechanisms. One is a rapid redistribution of the surface receptor into the interior of the cells, and the other is a decrease in the biosynthesis of the receptor. 59Fe from the internalized heme rapidly appeared in non-heme iron (ferritin) coincidently with the induction of heme oxygenase. The results suggest that iron released from heme down-regulates the expression of the transferrin receptors and iron uptake.

Biological Transport↗
PubMed1989

Changes in glycosylation alter the affinity of the human transferrin receptor for its ligand.

When transferrin receptors of human erythroleukemic cells were pulse-labeled with [35S]methionine and then chased in the absence of radioactive precursor, the first detectable immunoprecipitable form of the receptor had a molecular mass of 85 kDa. This form of the receptor was converted to the mature form of 93 kDa with a half-time of about 40-60 min. Both the immature (85 kDa) and mature (93 kDa) receptors associated as dimers, the native form of the receptor. The 85-kDa, as well as the 93-kDa, receptors bound to a monoclonal antibody raised against the transferrin receptor or to transferrin-Sepharose. In order to determine whether glycosylation was necessary for ligand binding, purified receptors were isolated from cells grown in the presence of tunicamycin. When K562 cells were grown in the presence of tunicamycin, an 80-kDa nonglycosylated form of the receptor was synthesized. This nonglycosylated receptor was also capable of dimer formation; however, much less of it reached the cell surface than the fully glycosylated form, although both untreated and tunicamycin-grown cells appeared to synthesize transferrin receptors at similar rates. Although the number of receptor molecules/cell was similar in control and tunicamycin-treated cells, the nonglycosylated receptors exhibited a much lower affinity for transferrin than those of untreated cells; in contrast, when receptors were purified by immunoprecipitation and digested with bacterial alkaline phosphatase, no difference was observed between the affinity of these receptors and undigested immunoprecipitated receptors. These results suggest that glycosylation is not necessary for specific binding of transferrin to its receptor, but the affinity of this binding can be influenced greatly by the presence or absence of carbohydrate residues.

Alkaline Phosphatase↗
PubMed1985

Inhibition of tumor cell growth by aggregation of a tumor-associated glycolipid antigen: a close functional association between gangliotriaosylceramide and transferrin receptor in mouse lymphoma L-5178Y.

The growth of mouse lymphoma L-5178Y cells with a high degree of gangliotriaosylceramide expression (high-expressor clone AA12) was inhibited by the addition of a biotinylated mouse immunoglobulin M monoclonal antibody (2D4) directed to gangliotriaosylceramide followed by cross-linking with avidin or a second antibody (anti-mouse immunoglobulin M). This growth inhibition was observed in both serum-containing medium and a chemically defined medium containing transferrin as the only growth factor. Cell growth was not inhibited by the addition of biotinylated antibody 2D4 alone, avidin alone, or the biotinylated derivative of an immunoglobulin M monoclonal anti-N-acetyllactosamine antibody (1B2) cross-linked with avidin. The growth of lymphoma L-5178Y 27AV cells, which do not express gangliotriaosylceramide (non-expressor clone), was not inhibited by either of these monoclonal antibodies or their biotinylated derivatives plus avidin. In the presence of biotinylated antibody 2D4 and avidin, cells of the high-expressor clone (L-5178Y AA12) displayed a capping of gangliotriaosyl antigen. In contrast, the transferrin receptor and the major glycoproteins (concanavalin A receptors) were not capped in the presence of biotinylated antibody 2D4 and avidin but were homogeneously distributed on the cell surface. Cells whose growth was inhibited by the addition of biotinylated antibody 2D4 and avidin showed an inhibition of 125I-transferrin internalization, although binding of 125I-transferrin to the cell surface was similar to that of control cells. These results indicate that the tumor antigen gangliotriaosylceramide is functionally associated with the transferrin receptor and may regulate the process of internalization of transferrin.

Animals↗
PubMed1986

Internalization and recycling of transferrin and its receptor. Effect of trifluoperazine on recycling in human erythroleukemic cells.

When human erythroleukemic (K562) cells were incubated with 25 microM trifluoperazine (TFP), a drug that inhibits both calmodulin-dependent and calcium-activated phospholipid-dependent kinases, the number of transferrin receptors detected on the cell surface was reduced to approximately half with no change in the affinity of the remaining surface receptors. Removal of the TFP from the incubation medium reversed the loss of surface receptors and they returned to the cell surface in an apparently synchronous manner. As a result, the number of receptors detected on the cell surface exceeded the original level but later returned to normal. Measurements of the total number of receptors available to transferrin in TFP-treated cells suggested that the lost receptors were not participating in the internalization and recycling pathway but instead were probably trapped at an intracellular location. However, those receptors that remained on the cell surface continued to internalize transferrin and to recycle apotransferrin to the cell surface albeit more slowly than in cells that had not been treated with TFP. Using transferrin that had been labeled with iron-59, it was found that although iron uptake was reduced in line with the diminished number of surface receptors, iron still accumulated within TFP-treated cells, suggesting that in the presence of the drug, transferrin-transferrin receptor complexes continued to migrate through an intracellular compartment that contained a low pH.

Cells, Cultured↗
PubMed1986

Identification of serine 24 as the unique site on the transferrin receptor phosphorylated by protein kinase C.

Addition of tumor-promoting phorbol diesters to [32P]phosphate-labeled A431 human epidermoid carcinoma cells caused an increase in the phosphorylation state of the transferrin receptor. The A431 cell transferrin receptor was also found to be a substrate for protein kinase C in vitro. Tryptic phosphopeptide mapping of the transferrin receptor resolved the same two phosphopeptides (X and Y) after either protein kinase C phosphorylation in vitro or treatment of labeled A431 cells with phorbol diesters. [32P]Phosphoserine was the only labeled phosphoamino acid detected. Phosphopeptide X was shown to be an incomplete tryptic digestion product which could be further digested with trypsin to generate the limit tryptic phosphopeptide (Y). Radiosequence analysis of [32P]phosphopeptide Y demonstrated that the [32P]phosphoserine was the second residue from amino terminus of the peptide. This receptor phosphopeptide was found to co-migrate with the synthetic peptide Phe-Ser(P)-Leu-Ala-Arg (where Ser(P) is phosphoserine) during reverse-phase high pressure liquid chromatography and two-dimensional thin layer electrophoresis and chromatography. The peptide Phe-Ser(P)-Leu-Ala-Arg is an expected tryptic fragment of the cytoplasmic domain of the transferrin receptor corresponding to residues 23-27. We conclude that the major site of protein kinase C phosphorylation of the transferrin receptor in vivo and in vitro is serine 24. This phosphorylation site is located within the intracellular domain of the transferrin receptor, 38 residues away from the predicted transmembrane domain.

Amino Acid Sequence↗
PubMed1987

Heterogeneous distribution of transferrin receptors on parenchymal and nonparenchymal liver cells: biochemical and morphological evidence.

To investigate which cells of the liver express the receptor for transferrin, isolated rat liver cells produced by collagenase perfusion were fractionated by repeated differential centrifugation to produce hepatocytes (95% + 1%, mean +/- SD, n = 4) and nonparenchymal cells (97% + 1%, n = 3). Saturable, high-affinity binding of 125I-transferrin was demonstrated on intact cells at 4 degrees C, with average receptor numbers 20,900 +/- 3,160 (mean + SD, n = 4) for hepatocytes and 5,500 + 1,520 (n = 3) for nonparenchymal cells. Total cellular receptors measured in detergent permeabilized hepatocytes were 42,000 +/- 18,330 (mean +/- SD, n = 3) per cell and 14,760 +/- 7,120 (n = 3) per cell in the nonparenchymal fraction. Immunocytochemical demonstration of transferrin using antitransferrin, peroxidase antiperoxidase complex confirmed that both cell types bound transferrin. There was heterogeneity of the staining reaction since there was no detectable staining on 40% of hepatocytes and 60% of nonparenchymal cells. Microdensitometric analysis of the staining product corroborated the biochemical evidence that hepatocytes have, on average, more than three times more transferrin receptors than do nonparenchymal cells. These findings support the concept that the hepatocyte has a central role in the uptake and storage of transferrin iron.

Animals↗
PubMed1984

Expression of the transferrin receptor in murine peritoneal macrophages is modulated in the different stages of activation.

A specific high affinity binding site for the serum glycoprotein transferrin was identified on murine peritoneal macrophages. The binding reached equilibrium within 60 min and was reversible, saturable, and specific for transferrin. Although the presence of this receptor was detected on the cell surface by studies carried out using intact cells, the majority (70 to 90%) of the binding activity was detectable only in detergent extracts of such cells. This suggests that a substantial portion of the binding activity is localized within the macrophage. The association constant (Ka) for binding to intact cells (6 to 9 X 10(8) M-1) was comparable to values reported for transferrin receptors described on other cell types. The expression of transferrin binding activity was examined in macrophages exhibiting qualitatively and quantitatively different degrees of functional activation. Resident peritoneal macrophages, exudate macrophages primed by elicitation with pyran copolymer, and activated macrophages induced by chronic infection of mice with bacillus Calmette-Guerin (BCG) or elicitation with heat killed Propionibacterium acnes (P. acnes) had low numbers of binding sites (1000 to 5000 total sites/cell). Macrophages elicited by sterile inflammatory agents (thioglycollate broth, fetal bovine serum, or casein) all exhibited a greater number of transferrin receptors (15,000 to 20,000 total sites/cell). This modulation did not appear to result from differential shifts between surface and internal loci. Our results suggest that the expression of the transferrin receptor may be a useful marker of the responsive stage of macrophage functional activation and the membrane changes that accompany activation.

Animals↗