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PubMed1993

Receptor-mediated endocytosis of a manganese complex of transferrin into neuroblastoma (SHSY5Y) cells in culture.

Exposure to manganese compounds often occurs as the result of industrial production or mining. Although manganese appears in traces in animal and human tissue and is essential to certain biological processes, it is also toxic. In humans and animals, toxicity is mainly associated with the nervous system. The mechanism underlying behavioral and biochemical alterations observed after manganese intoxication is not fully understood. We have shown that the manganese present in serum after exposure to manganese oxide is bound to transferrin as trivalent manganic ion. In this study of manganese uptake and storage we used a clone of human neuroblastoma cells (SHSY5Y). These cells differentiate and express catecholaminergic properties. Saturation binding analysis of the transferrin-manganese complex to the cells revealed a single class of binding sites, with an apparent KD of 13 +/- 1 nM and a density of 11,000 +/- 2,000 binding sites per cell. The complex was internalized in a temperature-dependent way and reached saturation after 2 h when approximately 2% of the added manganese had been internalized. About 80% of the internalized manganese was found in ferritin after 24 h of exposure. The results demonstrate that the transferrin receptor on SHSY5Y cells can bind and internalize a manganese-transferrin complex as efficiently as an iron-transferrin complex, although a saturation of the manganese uptake was achieved.

Chloroquine↗
PubMed1993

Characterization of the transferrin-iron uptake system in Neisseria meningitidis.

The transferrin-iron uptake system of six Neisseria meningitidis strains was characterized using 125I-transferrin in receptor assays and 55Fe-loaded transferrin in uptake assays. Receptors for transferrin varied among the strains both in number (from 700 to 4700 receptors per cell) and in their affinity constants for the protein (Ka ranged from 0.7 x 10(7) to 4.0 x 10(7) l mol-1). Neither receptor numbers nor affinity constants were significantly different in carrier and invasive strains, although the Ka seem to be somewhat higher in the latter. Iron uptake from transferrin was also variable among the strains, but showed the same lack of correlation with their origin.

Biological Transport, Active↗
PubMed1991

Evidence in support of the plasma membrane as the target for transferrin-adriamycin conjugates in K562 cells.

We have used transferrin-adriamycin conjugates to deliver drug to transferrin receptors and have shown that the conjugates bind to and kill tumor cells in vivo and in vitro. This has been studied with the use of qualitative and quantitative assays. In this report, we present evidence indicating that the primary target of transferrin-adriamycin cytotoxicity is the plasma membrane. This was done using a spectrofluorometric method that takes advantage of the fluorescence properties of adriamycin. It was shown that, while DNA intercalation may be the primary mechanism of cytotoxicity for free adriamycin, transferrin-adriamycin conjugates were not observed to interact with nuclear DNA. This may be a useful consideration in the design of future chemotherapeutic studies with transferrin conjugates of anticancer drugs.

Cell Division↗
PubMed1990

Iron acquisition in Pasteurella haemolytica: expression and identification of a bovine-specific transferrin receptor.

Seven type 1 field isolates of Pasteurella haemolytica were screened for their ability to use different transferrins as a source of iron for growth. All seven strains were capable of using bovine but not human, porcine, avian, or equine transferrin. A screening assay failed to detect siderophore production in any of the strains tested. Iron-deficient cells from these strains expressed a binding activity, specific for bovine transferrin, that was regulated by the level of iron in the medium. Inhibition of expression by translation and transcription inhibitors suggested that iron regulation was occurring at the gene level. Affinity isolation of receptor proteins from all seven strains with biotinylated bovine transferrin identified a 100-kilodalton iron-regulated outer membrane protein as the bovine transferrin receptor. Iron-regulated outer membrane proteins of 71 and 77 kilodaltons were isolated along with the 100-kilodalton protein when less stringent washing procedures were employed in the affinity isolation procedure.

Animals↗
PubMed1995

Identification and characterization of genes encoding the human transferrin-binding proteins from Haemophilus influenzae.

Haemophilus influenzae, a strict human pathogen, acquires iron in vivo through the direct binding and removal of iron from human transferrin by an as yet uncharacterized process at the bacterial cell surface. In this study, the tbpA and tbpB genes of H. influenzae, encoding the transferrin-binding proteins Tbp1 and Tbp2, respectively, were cloned and sequenced. Alignments of the H. influenzae Tbp1 and Tbp2 protein sequences with those of related proteins from heterologous species were analyzed. On the basis of similarities between these and previously characterized proteins, Tbp1 appears to be a member of the TonB-dependent family of outer membrane proteins while Tbp2 is lipid modified by signal peptidase II. Isogenic mutants deficient in expression of Tbp1 or Tbp2 or both proteins were prepared by insertion of the Tn903 kanamycin resistance cassette into cloned sequences and reintroduction of the interrupted sequences into the wild-type chromosome. Binding assays with the mutants showed that a significant reduction in transferrin-binding ability resulted from the loss of either of the Tbps and a complete loss of binding was evident when neither protein was expressed. Loss of either Tbp2 or both proteins correlated with an inability to grow on media supplemented with transferrin-bound iron as the sole source of iron, whereas the Tbp1+ Tbp2- mutant was able to grow only at high transferrin concentrations.

Amino Acid Sequence↗
PubMed1999

The staphylococcal transferrin-binding protein is a cell wall glyceraldehyde-3-phosphate dehydrogenase.

Staphylococcus aureus and Staphylococcus epidermidis possess a 42-kDa cell wall transferrin-binding protein (Tpn) which is involved in the acquisition of transferrin-bound iron. To characterize this protein further, cell wall fractions were subjected to two-dimensional sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis blotted, and the N-terminus of Tpn was sequenced. Comparison of the first 20 amino acid residues of Tpn with the protein databases revealed a high degree of homology to the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Analysis of staphylococcal cell wall fractions for GAPDH activity confirmed the presence of a functional enzyme which, like Tpn, is regulated by the availability of iron in the growth medium. To determine whether Tpn is responsible for this GAPDH activity, it was affinity purified with NAD+ agarose. Both S. epidermidis and S. aureus Tpn catalyzed the conversion of glyceraldehyde-3-phosphate to 1,3-diphosphoglycerate. In contrast, Staphylococcus saprophyticus, which lacks a Tpn, has no cell wall-associated GAPDH activity. Native polyacrylamide gel electrophoresis of the affinity-purified Tpn revealed that it was present in the cell wall as a tetramer, consistent with the structures of all known cytoplasmic GAPDHs. Furthermore, the affinity-purified Tpn retained its ability to bind human transferrin both in its native tetrameric and SDS-denatured monomeric forms. Apart from interacting with human transferrin, Tpn, in common with the group A streptococcal cell wall GAPDH, binds human plasmin. Tpn-bound plasmin is enzymatically active and therefore may contribute to the ability of staphylococci to penetrate tissues during infections. These studies demonstrate that the staphylococcal transferrin receptor protein, Tpn, is a multifunctional cell wall GAPDH.

Amino Acid Sequence↗
PubMed1984

The fate of the transferrin receptor during maturation of sheep reticulocytes in vitro.

The transferrin receptor of sheep reticulocytes is excised from the cell during in vitro maturation to erythrocytes. The excised receptor may be recovered from the medium by centrifugation at 100 000 X g. Loss of transferrin-binding activity parallels the loss of binding of anti-receptor antibody, as well as RNA content. The released receptor retains the molecular size of the receptor isolated from the plasma membranes (93 000 monomer, 186 000 dimer), has an identical iodotyrosyl peptide map, and is still capable of binding transferrin, as well as an antibody directed against the receptor. The receptor is released in a vesicular form. The major peptides of the vesicles are the receptor and an unidentified peptide of 70 000 whose iodotyrosyl peptide map is distinct from that of the receptor. Although the transferrin receptor has been shown to undergo posttranslational modification (phosphorylation, acylation, and glycosylation) in cultured cells, it has not been established whether any of the transformations are retained in nongrowing cells. In the present communication, it is shown that isolated reticulocyte plasma membranes are capable of receptor phosphorylation, a process previously shown only with intact, cultured cells. The phosphorylating activity is retained in immunoprecipitates of the receptor, but is absent in the vesicles released during maturation. No evidence has been obtained for an effect of either transferrin or an anti-receptor antibody on receptor phosphorylation in intact cells or isolated membranes.

Animals↗
PubMed1992

Hepatic heparan sulphate proteoglycan and the recycling of transferrin.

Heparan sulphate proteoglycan, labelled with [35S]sulphate, was prepared from rat livers for studies of its interaction with purified rat transferrin. Affinity chromatography of the preparation on columns of immobilized differic transferrin and apotransferrin showed that the proteoglycan possessed affinity for both types of matrices at pH 7.3 and that this affinity significantly increased at pH 5.6. The glycosaminoglycan chains liberated from the proteoglycan by heparan sulphate lyase also bound to apotransferrin, albeit less strongly, whereas the deglycosylated core protein exhibited virtually no interaction with this matrix. In the presence of the proteoglycan at pH 5.6, the release of iron from the N-lobe of transferrin was accelerated. These observations suggest that heparan sulphate proteoglycan from the liver can mimick some of the known functions of bona fide transferrin receptors and, hence, interaction with the proteoglycan may provide an alternative nondegradative pathway for transferrin through hepatic cells.

Animals↗
PubMed1980

Transferrin binding to peripheral blood lymphocytes activated by phytohemagglutinin involves a specific receptor. Ligand interaction.

Immunohistological studies have indicated that membrane sites binding transferrin are present upon activated human peripheral blood lymphocytes. In this study, we have investigated transferrin uptake in human lymphocytes exposed to phytohemagglutinin (PHA), by quantitative radiobinding and immunofluorescence in parallel. In stimulated lymphocytes, binding was maximal after a 30-min incubation, being greatest at 37 degrees C, and greater at 22 degrees C than at 4 degrees C. Although some shedding and endocytosis of transferrin occurred at 22 degrees and 37 degrees C, these factors, and resulting synthesis of new sites, did not affect measurement of binding which was found to be saturable, reversible, and specific for transferrin (K(a) 0.5-2.5 x 10(8) M(-1)). Binding was greater after a 48-h exposure to PHA than after 24 h, and was maximal at 66 h. Sequential Scatchard analysis revealed no significant elevation in affinity of interaction. However, although the total number of receptors increased, the proportion of cells in which binding of ligand was detected immunohistologically increased in parallel, and after appropriate correction, the cellular density of receptors remained relatively constant throughout (60,000-80,000 sites/cell). Increments in binding during the culture period were thus due predominantly to expansion of a population of cells bearing receptors. Similar differences in binding were apparent upon comparison of cells cultured in different doses of PHA, and in unstimulated cells binding was negligible. Transferrin receptors appear, therefore, to be readily detectable only upon lymphocytes that have been activated.

Dose-Response Relationship, Drug↗
PubMed1985

Ultrastructural immunocytochemical localization of the transferrin receptor using a monoclonal antibody in human KB cells.

Using a monoclonal antibody (HB21) against the human transferrin receptor, we have localized this receptor in cultured KB human carcinoma cells by fluorescence and ultrastructural immunocytochemistry. The receptor was found diffusely distributed on the cell surface, concentrated in clathrin-coated pits of the cell surface, in intracellular endocytic vesicles (receptosomes) derived from coated pits, in tubular elements of the trans-reticular Golgi system, and in microtubule-associated membranous elements thought to be part of the constitutive exocytic system. This distribution is the same as that previously shown for labeled transferrin in these same cells (Willingham MC, Hanover JA, Dickson BB, Pastan J: Proc Natl Acad Sci USA 81:175, 1984). No significant amounts of receptor were found in lysosomes. An aggregation of membranous elements containing this receptor was found in the pericentriolar region of cells during mitosis. Together with the previous data on the immunocytochemical localization of transferrin, these results suggest that the transferrin receptor may constitutively enter and exit KB cells by endocytosis and exocytosis, carrying bound transferrin into and out of the cell for the purpose of supplying iron from the extracellular environment for cell growth.

Antibodies, Monoclonal↗
PubMed1998

Production and characterization of fusion proteins containing transferrin and nerve growth factor.

To explore the ability to use genetic fusions of transferrin as a carrier for brain targeting and delivery, a series of fusion proteins containing both human nerve growth factor (NGF) and human transferrin was produced in mammalian cells. A protein in which the hinge region from human IgG3 joined the carboxyl terminus of NGF and the amino terminus of transferrin formed a covalent homodimer, bound human transferrin receptor, and retained full NGF in PC12 cells. In contrast, proteins in which polypeptide dimerization was not induced or in which NGF was fused through its amino terminus had greatly reduced NGF activity. The ability to maintain both biologically active NGF and transferrin as part of a fusion protein may offer a novel way to deliver NGF and other neurotrophic factors to the central nervous system.

Blood-Brain Barrier↗
PubMed2002

[Preparation, characterization and receptor-binding capacity of pig serum transferrin half-molecules containing a single iron-binding site].

N- and C-half molecules containing a single iron-binding site were simultaneously obtained from trypsin digest of iron-saturated pig transferrin. The activities of the pig serum transferrin and of its N- and C-half molecules to bind the human placental membrane transferrin receptor were compared. The results indicate that the receptor-binding site of pig transferrin may be located at the C-half molecule of the transferrin.

Amino Acids↗
PubMed1988

Preliminary evaluation of platinum transferrin (MPTC-63) as a potential nontoxic treatment for breast cancer.

Transferrin receptors on proliferating and malignant cells are well documented. Faulk et al. demonstrated transferrin receptors in breast carcinoma by immunofluorescence. Malignant cells requiring more iron modulate a transferrin receptor and the iron transporting protein transferrin delivers iron to the cell. We have developed a physiologically active platinum transferrin complex that has been tested on several cell lines in culture, a tumor model in the Fischer rat, and five human patients with advanced breast carcinoma. The complex slowed the rate of growth of feline lymphoma cells to one-half that of controls and killed human HeLa cell cultures in 7 days. Growth of the rat tumor was slightly impaired, but treated rats never got systemic disease and controls died. Two patients had dramatic responses to treatment. One had systemic disease and the other advanced locoregional disease. Both patients were on Tamoxifen, as receptors were positive for estrogen. Disease was progressing in the former with little improvement in the latter. After treatment both had a marked response. We postulate that MPTC-63 may work synergistically with Tamoxifen and be an effective nontoxic antitumor agent. More studies are indicated.

Animals↗
PubMed1987

Inhibition of hemoglobin production by transferrin-gallium.

Recent clinical trials evaluating gallium nitrate as a chemotherapeutic agent have reported the development of microcytic hypochromic anemia in patients treated with this agent. Because gallium is known to bind avidly to transferrin, we examined the effect of transferrin-gallium (Tf-Ga) on hemoglobin production by Friend erythroleukemia cells in vitro. Cellular hemoglobin production, as assessed by benzidine staining, cellular hemoglobin content, and 59Fe incorporation into heme, was significantly decreased following exposure of cells to Tf-Ga. Tf-Ga led to an early decrease in cellular 59Fe incorporation even before changes in hemoglobin production were detected. A marked increase in cellular transferrin receptor expression occurred following exposure of cells to Tf-Ga. Tf-Ga inhibition of hemoglobin production could be reversed and hemoglobin production could be restored to normal by addition to the media of either transferrin-iron (Tf-Fe) or iron-pyridoxal isonicotinoyl hydrazone, a compound capable of supplying iron directly to reticulocytes for heme synthesis without transferrin as a mediator. These studies provide an explanation for the development of anemia in patients treated with gallium nitrate and suggest that gallium's mechanism of chemotherapeutic action includes inhibition of cellular iron incorporation.

Anemia, Hypochromic↗
PubMed1980

Metabolic and cytoskeletal modulation of transferrin receptor mobility in mitogen-activated human lymphocytes.

The transferrin receptors which appear on mitogen-activated human peripheral blood lymphocytes were found by the use of immunofluorescence techniques to display temperature-dependent patching and capping reactions upon binding of transferrin. Lateral mobility of ligand-occupied membrane sites was accompanied by both shedding and endocytosis of receptor-transferrin complexes. In the presence of sodium azide or the microfilament inhibitor cytochalasin B, cap formation and shedding were markedly inhibited. In contrast, endocytosis of patched receptor-ligand complexes was inhibited by azide and microtubule inhibitors, including colchicine, vinblastine and vincristine. Co-capping experiments performed to elucidate further the alterations in membrane configuration involved in these reactions failed to reveal any topographical relationship between transferrin receptors and lectin-binding sites in these cells. These studied indicate that temperature-dependent mobility of transferrin receptors upon mitogen-activated peripheral blood lymphocytes is dependent upon the integrity of the cytoskeletal system and metabolic function of the cell.

Binding Sites↗
PubMed1982

Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9.

The monoclonal antibody OKT9 reacts specifically with the receptors for transferrin on human cells (Sutherland, D. R., Delia, D., Schneider, C., Newman, R. A., Kemshead, J., and Greaves, M. F. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 4515-4519; in Leukemia Markers (Knapp, W., ed) pp. 157-160, Academic Press, New York) and has been used to isolate and characterize this receptor. The receptor is a dimeric glycoprotein (Mr = 180,000) composed of two subunits (Mr = 90,000) and has a pI of approximately 5.2. The transferrin receptor appears to be a transmembrane molecule and is phosphorylated, the phosphate group being predominantly on serine residues. The cell surface form of the molecular possesses both complex and high mannose oligosaccharide chains, which do not appear to have a direct role in antibody (OKT9) binding. The molecule can be cleaved into a Mr = 70,000 fragment from the cell surface, suggesting that the major part of the receptor is exposed to the extracellular environment. The released Mr = 70,000 fragments are not disulfide-linked and possess the antibody (OKT9)- and transferrin-binding sites. Cross-linking studies using radiolabeled transferrin suggest that two molecules of transferrin are bound to each Mr = 180,000 receptor dimer.

Antibodies, Monoclonal↗
PubMed1983

Molecular identification of the TCA alloantigen as the transferrin receptor on T-cells of a leukemic patient with serum from a monozygotic twin brother.

The transferrin receptor is encoded by a diallelic locus which had been described as the T-cell antigenic system TCA. Using a human lymphoblastoid T-cell line (HSB) which reportedly carries a transferrin receptor and which we showed to be TCA-2 positive by serology, it appeared that only a TCA-2 but not a TCA-1 specific alloantiserum had the capacity to precipitate a protein with a molecular weight of 94,000, which comigrated exactly with the Mr 94,000 protein precipitated by the rabbit anti-HSB and rabbit anti-SB antisera, as well as the transferrin receptor which was precipitated by a transferrin-antitransferrin complex. The positive sera and the latter complex were shown to cross-react in a binding assay. Conversely, a monospecific TCA-1 alloantiserum was shown to react with the Mr 94,000 protein of TCA-1-positive leukocyte suspensions. The allelomorphism of the transferrin receptor may be relevant for the eventual regulatory mechanism controlling cell proliferation, which would be essential at least for those cells that are supposed to play an immunological role like the TCA-positive cells which are described as T-cells probably involved in the process of immunosuppression. In addition, we found increasing amounts of autoantibodies with TCA-1 specificity in serum from a healthy individual (referred to as "donor" in this paper), whose brother at the same time suffered a chronic myeloid leukemia, probably associated with a retrovirus, and whose blood in contrast was shown to contain cytotoxic anti-TCB, from a diallelic locus expressed on theophylline-insensitive T-cells, and anti-B-cell activity.

Adult↗
PubMed1983

Chromosome 3q (22-ter) encodes the human transferrin receptor.

The human transferrin receptor is an integral membrane glycoprotein of 180,000 molecular weight (mol. wt.) formed from two subunits of 90,000 mol. wt. A clone panel of Chinese hamster-human somatic cell hybrids was screened using a single cell plating cytotoxicity assay and rabbit antiserum raised to purified human transferrin receptor. Chromosome 3 displayed the highest rate of concordance with the presence of human transferrin receptor, as assayed by cytotoxicity. Antitransferrin receptor serum-resistant segregants of chromosome 3 positive, receptor-positive hybrids were selected, using antiserum and complement. The segregants consistently lost chromosome 3. 125I human transferrin binding studies confirmed synteny between the functional human transferrin receptor and chromosome 3. Examination of hybrids with either translocated or deleted chromosome 3's allows regional mapping to 3q(22-ter).

Animals↗