Transferrin receptor-mediated endocytosis

Qian, Z.M., et al. 2002. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev 54 561. 

The observations described above have important implications with regard to actinide/lanthanide distributions within the body. It is apparent that in binding to transferrin, the f elements are participating in certain aspects of the iron transport pathways in vivo. However, no plutonium, e.g., is found within red blood cells following incorporation and there is no unequivocal evidence that plutonium and the other actinides or lanthanides are transported into cells via transferrin-receptor-mediated endocytosis (Duffield and Taylor 1986). This, too, is a puzzling aspect of f-element-transferrin chemistry and biochemistry which needs more study. 

There are receptors (TfRs) on the surfaces of many cells for transferrin, it binds to these receptors and is internalized by receptor-mediated endocytosis (compare the fate of LDL Chapter 25). The acid pH inside the lysosome causes the iron to dissociate from the protein. The dissociated iron leaves the endosome via DMTl to enter the cytoplasm. Unlike the protein component of LDL, apoTf is not degraded within the lysosome. Instead, it remains associated with its receptor, returns to the plasma membrane, dissociates from its receptor, reenters the plasma, picks up more iron, and again delivers the iron to needy ceils. 

Transferrin iron uptake via receptor-mediated endocytosis has clearly appeared fairly late in evolution, when we consider that the bilobal iron-binding protein is found only as far back as insects . As we have seen in the preceding chapters, iron-uptake mechanisms involving the synthesis of more or less specific siderophores have evolved together with strategies implying the solubilization of insoluble ferric iron by the combined effects of pH and reduction, and even the development of receptor proteins capable of taking up transferrin-, lactoferrin- or haem-bound iron from specific hosts. 

Figure 11.1 Schematic representation of iron uptake mechanisms, (a) The transferrin-mediated pathway in animals involves receptor-mediated endocytosis of diferric transferrin (Tf), release of iron at the lower pH of the endocytic vesicle and recycling of apoTf. (b) The mechanism in H. influenzae involves extraction of iron from Tf at outer membrane receptors and transport to the inner membrane permease system by a periplasmic ferric binding protein (Fbp). From Baker, 1997. Reproduced by permission of Nature Publishing Group.

Wagner E, Curiel D, Cotten M (1994) Delivery of drugs, proteins and genes into cells using transferrin as a ligand for receptor-mediated endocytosis. Adv Drug Del Rev 14 113-136... 

Zenke M, Steinlein P, Wagner E, Cotten M, Beug H, Bimstiel ML (1990) Receptor-mediated endocytosis of transferrin-polycation conjugates an efficient way to introduce DNA into hematopoietic cells. Proc Natl Acad Sci USA 87 3655-3659... 

Many of the investigations into endosomal pathways have concentrated on receptor-mediated endocytosis, as in the iron-transferrin-receptor complex, and it is not clear how the systems vary depending on whether or not the pathway is clathrin-dependent or clathrin-independent [54],... 

However, the receptor-mediated endocytosis of iron-transferrin studies [63] does not explain the initial uptake of iron from nutrients in the intestinal (villus) cells, since apotransferrin is generally not available in the lumen, except in a limited amount from biliary excretion. Work on other iron transport mechanisms has mainly been reported in the last five years. 

QDs recognized specific antigens/antibodies -DNA immobilization to QDs surfaces and possibility of hybrid assemblies [35] -Coupled to transferrin, QDs underwent receptor-mediated endocytosis in cultured HeLa cells... 

Karin M, Mintz B. Receptor-mediated endocytosis of transferrin in developmen-tally totipotent mouse teratocarcinoma stem cells. J Biol Chem 1981 256(7) ... 

The process of transcytosis is illustrated in Figure 2.3 for the transferrin receptor (TfR) [37]. The receptor is heavily expressed at the BBB compared to other vascular beds [38]. Transferrin or a monoclonal antibody to the extracellular domain of the receptor protein will bind from the luminal side of the BBB. This triggers cellular uptake by the mechanism of receptor-mediated endocytosis, i.e. the invagination and budding off of parts of the cell membrane as a result of the formation of small vesicles (endosomes). The transceUular passage of ligand (transcytosis) is completed by exocytosis at the abluminal membrane, and the whole process is completed within minutes in vivo. 

Receptor mediated endocytosis, on the other hand, requires recognition by the receptor before internalization of the molecule. So far, two receptor mediated endocytosis protocols have mainly been studied for potential applications in MRI contrast enhancement, namely the transferrin and folic acid receptor systems. 

Weissleder et al. [84] first showed that the human transferrin receptor (hTfR) can be used to internalize MRI contrast agents. The hTfR regulates cellular uptake of iron from transferrin, a plasmatic iron transport protein [85], via a receptor mediated endocytosis mechanism. Thus, MION particles (dextran coated iron oxide) were oxidized with sodium periodate. Holotransferrin was added and the resulting Schiff base adduct was reduced with sodium cyanoborohydride to give transferrin labeled MIONs, Tf-MION (Scheme 3). 

Larrick, J.W., C. Enns, A. Raubitschek, and H. Weintraub. 1985. Receptor-mediated endocytosis of human transferrin and its cell surface receptor. J Cell Physiol 124 283. 

Transferrin is a single-chain glycoprotein which has two similar binding sites for Fem ions situated in interdomain clefts in the N-terminal half (N-lobe) and C-terminal half of the molecule. Diferric transferrin is taken up by cells via receptor-mediated endocytosis. It is possible that transferrin delivers Pt to tumor cells which are known to overexpress such receptors. The combination of 1H-, 15N- and 13C-NMR spectroscopy (15N-cisplatin and 13C-Met-transferrin) has shown that one of the major cisplatin binding sites is Met-256 in the N-lobe which is solvent-accessible [51]. 

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