Transferrin receptor (TfR) is a carrier protein for transferrin. It is needed for the import of iron into the cell and is regulated in response to intracellular iron concentration. It imports iron by internalizing the transferrin-iron complex through receptor-mediated endocytosis. The existence of a receptor for transferrin iron uptake had been recognized over half a century back.Earlier two transferrin receptors in humans, transferrin receptor 1 and transferrin receptor 2 had been characterized and till recently cellular iron uptake was believed to occurs chiefly via these two well documented transferrin receptors. Both these receptors are transmembrane, glycoproteins. TfR1 is a high affinity ubiquitously expressed receptor while expression of TfR2 is restricted to certain cell types and is unaffected by intracellular iron concentrations. TfR2 binds to transferrin with a 25-30 fold lower affinity than TfR1. Although TfR1 mediated iron uptake is the major pathway for iron acquisition by most cells and especially developing erythrocytes, several studies have indicated that the uptake mechanism varies depending upon the cell type. It is also reported that Tf uptake, independent of these TfR’s exists although the mechanisms are not well characterized. The multifunctional glycolytic enzyme Glyceraldehyde 3-phosphate dehydrogenase (GAPDH,EC 18.104.22.168) has been shown to utilize post translational modifications to exhibit higher order moonlighting behavior wherein it switches its function as a holo or apo transferrin receptor leading to either iron delivery or iron export respectively
Low iron concentrations promote increased levels of transferrin receptor, to increase iron intake into the cell. Thus, transferrin receptor maintains cellular iron homeostasis.
TfR production in the cell is regulated according to iron levels by iron-responsive element-binding proteins, IRP1 and IRP2. In the absence of iron, one of these proteins (generally IRP2) binds to the hairpin like structure (IRE) that is in the 3' UTR of the TfR receptor mRNA. Once binding occurs, the mRNA is stabilized and degradation is inhibited.
^Jandl JH, Inman JK, Simmons RL, Allen DW. Transfer of iron from serum iron-binding protein to human reticulocytes. J Clin Invest 1959;38(1, Part 1):161-85.
^Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem 2000;275(22):16618-25.
^West AP, Jr., Bennett MJ, Sellers VM, Andrews NC, Enns CA, Bjorkman PJ. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. J Biol Chem 2000;275(49):38135-8.
^K. Gkouvatsos, G. Papanikolaou, K. Pantopoulos, Regulation of iron transport and the role of transferrin, Biochim. Biophys. Acta, 1820 (2012) 188-202.
^D. Trinder, O. Zak, P. Aisen, Transferrin receptor-independent uptake of differic transferrin by human hepatoma cells with antisense inhibition of receptor expression, Hepatology, 23 (1996) 1512-1520.
^R. Kozyraki, J. Fyfe, P.J. Verroust, C. Jacobsen, A. Dautry-Varsat, J. Gburek, T.E. Willnow, E.I. Christensen, S.K. Moestrup, Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia, Proceedings of the National Academy of Sciences, 98 (2001) 12491-12496.
^J. Yang, D. Goetz, J.-Y. Li, W. Wang, K. Mori, D. Setlik, T. Du, H. Erdjument-Bromage, P. Tempst, R. Strong, J. Barasch, An Iron Delivery Pathway Mediated by a Lipocalin, Mol. Cell, 10 (2002) 1045-1056.
^M. A. Sirover, Structural analysis of glyceraldehyde-3-phosphate dehydrogenase functional diversity The International Journal of Biochemistry & Cell Biology 57 (2014) 20–26.
^V. M. Boradia, M. Raje and C.I. Raje, Protein moonlighting in iron metabolism: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Biochemical Society Transactions; 2014, 42(6): 1796-1801.
Testa U, Kühn L, Petrini M, Quaranta MT, Pelosi E, Peschle C (July 1991). "Differential regulation of iron regulatory element-binding protein(s) in cell extracts of activated lymphocytes versus monocytes-macrophages". J. Biol. Chem.266 (21): 13925–30. PMID1856222.
Daniels TR, Delgado T, Helguera G, Penichet ML (November 2006). "The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells". Clin. Immunol.121 (2): 159–76. doi:10.1016/j.clim.2006.06.006. PMID16920030.