Transferrin receptor pathway

Once in the serum, aluminium can be transported bound to transferrin, and also to albumin and low-molecular ligands such as citrate. However, the transferrrin-aluminium complex will be able to enter cells via the transferrin-transferrin-receptor pathway (see Chapter 8). Within the acidic environment of the endosome, we assume that aluminium would be released from transferrin, but how it exits from this compartment remains unknown. Once in the cytosol of the cell, aluminium is unlikely to be readily incorporated into the iron storage protein ferritin, since this requires redox cycling between Fe2+ and Fe3+ (see Chapter 19). Studies of the subcellular distribution of aluminium in various cell lines and animal models have shown that the majority accumulates in the mitochondria, where it can interfere with calcium homeostasis. Once in the circulation, there seems little doubt that aluminium can cross the blood-brain barrier. 

Another potential source of iron, at least for hepatocytes, is receptor-independent uptake of iron from transferrin. This appears to involve an iron uptake pathway from transferrin which is neither suppressed in hepatocytes by antibodies to TfR (Trinder et at, 1988), nor by transfection of HuH-7 hepatoma cells with transferrin receptor anti-sense cDNA (Trinder etat, 1996). The same pathway may also be utilized for iron uptake from isolated transferrin N-lobe, which is not recognized by the receptor (Thorstensen et at, 1995). The possible role of TfR2 in this process remains to be established, as does the physiological importance of this pathway in intact liver. Human melanoma cells (Richardson and Baker, 1994) and Chinese hamster cells lacking transferrin receptors but transfected with melanotransferrin (Kennard et at, 1995) use another pathway for transferrin iron uptake, independent of the transferrin receptor, but utilizing iron transfer from transferrin or simple iron chelates to membrane-anchored melanotransferrin, and from there onwards into the cellular interior. 

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.

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],... 

The uptake of iron into the cell could follow several pathways. The iron could be released from the transferrin at the receptor site and be carried into the cell. Alternatively, the whole transferrin-receptor complex could be taken into the cell via endocytosis, and passed into an acidic compartment, where the iron is released, passed out of the compartment, and stored in ferritin. 

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

Polypeptides are substrates for receptor-mediated transcytosis. Cerebral insulin reaches the brain from the circulation via receptor-mediated transcytosis through the BBB on the brain endothelial insulin receptor. This receptor is upregulated in development and downregulated in streptozotocin-induced diabetes mellitus. Similarly a BBB transferrin receptor mediates the transcytosis of transferrin across the BBB and this explains how the brain is able to extract iron from the circulation. Other RMT pathways consituting portals of entry to the brain for circulating peptides include receptors for insulin-like growth factors, cationic proteins, lectins, acetyl-low density lipoprotein and leptin. 

The exclusive presence of lanthanum in the bile and in the lysosomes of the liver cell is consistent with excretion of lanthanum by the liver via the transferrin receptor-endosomal-lysosomal-bile canaliculus pathway [41]. Clinical studies of up to 4 years have not... 

When iron is low in the cell, the mRNA for ferritin is translated at a lesser rate (resulting in lesser amoimts of this protein in the cell). The goal here is to cut down on the excessive synthesis of our major iron storage protein, if no excess iron is available for storing. When iron is low in the cell, the mRNA for the transferrin receptor is translated more (creating more transferrin). When iron is low in the cell, the mRNA for 5-aminolevulinate synthase, an enz)mie in the heme biosynthetic pathway, is translated less. The overall goal here is to cut down on the wasteful synthesis of heme, if no iron is available for completing this cofactor. 

Anti-transferrin receptor/anti-DT bispecific antibodies were used to deliver CRM107 into cells via the transferrin pathway and to demonstrate that the acid-release mechanism was functioning properly. This receptor was targeted because it normally cycles protein-bound iron through acidic endosomes where the Fe3+ is released by the low pH (26). The dual binding capacity of the bispecific antibodies was confirmed by their ability to specifically deliver [125I]-diphtheria toxin to transferrin receptors present on intact human cells. 

The role of melanotransferrin has been recently elucidated by Kennard et al. [207] who demonstrated that this membrane bound iron binding protein is involved in the transferrin-independent uptake of iron in mammals but from iron-citrate and not from iron-transferrin complexes. This alternative iron uptake pathway may not function in the normal recirculation of iron within the body but might play a role during iron overload. On the other hand, rapidly proliferative tumor cells like melanocytes could use the alternative pathway to increase iron uptake. This independent system could also participate in the absorption of iron by intestinal cells that have no transferrin receptor on their lumenal surfaces [208], but express a transferrin-like GPI-linked iron-binding protein at the apical surface of fetal intestinal epithelial cells [209]. 

Steady-state levels of RNA can be controlled by balancing rates of synthesis and degradation. Both endoribonucleases and exoribonucleases play a role in RNA degradation pathways. Control of transferrin-receptor mRNA levels by cytoplasmic aconitase/IRE-BP activities is a classic example of regulation of RNA turnover rates in response to physiological signals. 

Binder R, Horowitz J. A., Basilion J. P., Koeller D. M., Klausner R. D., Harford J. B. (1994) Evidence that the pathway of transferrin receptor mRNA degradation involves an endonucleolytic cleavage within the 30 UTR and does not involve poly(A) tail shortening. EMBO J 13 1969. 

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