Transferrin receptor (TfR) is a carrier protein for transferrin. It is needed for the import of iron into cells and is regulated in response to intracellular iron concentration. It imports iron by internalizing the transferrin-iron complex through receptor-mediated endocytosis.[1] The existence of a receptor for transferrin iron uptake has been recognized since the late 1950s.[2] Earlier two transferrin receptors in humans, transferrin receptor 1 and transferrin receptor 2 had been characterized and until recently cellular iron uptake was believed to occur 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.[3][4] 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 exists independent of these TfRs although the mechanisms are not well characterized.[5][6][7][8] The multifunctional glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12) 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.[9][10][11]
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 mRNA. Once binding occurs, the mRNA is stabilized and degradation is inhibited.
^Qian ZM, Li H, Sun H, Ho K (December 2002). "Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway". Pharmacological Reviews. 54 (4): 561–87. doi:10.1124/pr.54.4.561. PMID 12429868. S2CID 12453356.; Figure 3: The cycle of transferrin and transferrin receptor 1-mediated cellular iron uptake.
^Jandl JH, Inman JK, Simmons RL, Allen DW (January 1959). "Transfer of iron from serum iron-binding protein to human reticulocytes". The Journal of Clinical Investigation. 38 (1, Part 1): 161–85. doi:10.1172/JCI103786. PMC444123. PMID 13620780.
^Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP (June 2000). "Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo". The Journal of Biological Chemistry. 275 (22): 16618–25. doi:10.1074/jbc.M908846199. PMID 10748106.
^West AP, Bennett MJ, Sellers VM, Andrews NC, Enns CA, Bjorkman PJ (December 2000). "Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE". The Journal of Biological Chemistry. 275 (49): 38135–8. doi:10.1074/jbc.C000664200. PMID 11027676.
^Gkouvatsos K, Papanikolaou G, Pantopoulos K (March 2012). "Regulation of iron transport and the role of transferrin". Biochimica et Biophysica Acta (BBA) - General Subjects. 1820 (3): 188–202. doi:10.1016/j.bbagen.2011.10.013. PMID 22085723.
^Trinder D, Zak O, Aisen P (June 1996). "Transferrin receptor-independent uptake of differic transferrin by human hepatoma cells with antisense inhibition of receptor expression". Hepatology. 23 (6): 1512–20. doi:10.1053/jhep.1996.v23.pm0008675172. PMID 8675172.
^Kozyraki R, Fyfe J, Verroust PJ, Jacobsen C, Dautry-Varsat A, Gburek J, Willnow TE, Christensen EI, Moestrup SK (October 2001). "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 of the United States of America. 98 (22): 12491–6. Bibcode:2001PNAS...9812491K. doi:10.1073/pnas.211291398. PMC60081. PMID 11606717.
^Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J (November 2002). "An iron delivery pathway mediated by a lipocalin". Molecular Cell. 10 (5): 1045–56. doi:10.1016/s1097-2765(02)00710-4. PMID 12453413.
^Sirover MA (December 2014). "Structural analysis of glyceraldehyde-3-phosphate dehydrogenase functional diversity". The International Journal of Biochemistry & Cell Biology. 57: 20–6. doi:10.1016/j.biocel.2014.09.026. PMC4268148. PMID 25286305.
^Boradia VM, Raje M, Raje CI (December 2014). "Protein moonlighting in iron metabolism: glyceraldehyde-3-phosphate dehydrogenase (GAPDH)". Biochemical Society Transactions. 42 (6): 1796–801. doi:10.1042/BST20140220. PMID 25399609.
^Sheokand N, Malhotra H, Kumar S, Tillu VA, Chauhan AS, Raje CI, Raje M (October 2014). "Moonlighting cell-surface GAPDH recruits apotransferrin to effect iron egress from mammalian cells" (PDF). Journal of Cell Science. 127 (Pt 19): 4279–91. doi:10.1242/jcs.154005. PMID 25074810. S2CID 9917899.
Further readingedit
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". The Journal of Biological Chemistry. 266 (21): 13925–30. doi:10.1016/S0021-9258(18)92790-0. PMID 1856222.
Daniels TR, Delgado T, Rodriguez JA, Helguera G, Penichet ML (November 2006). "The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer". Clinical Immunology. 121 (2): 144–58. doi:10.1016/j.clim.2006.06.010. PMID 16904380.; Figure 3: Cellular uptake of iron through the Tf system via receptor-mediated endocytosis.
Daniels TR, Delgado T, Helguera G, Penichet ML (November 2006). "The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells". Clinical Immunology. 121 (2): 159–76. doi:10.1016/j.clim.2006.06.006. PMID 16920030.
Okam M (2001-01-29). "Iron Transport and Cellular Uptake". Information Center for Sickle Cell and Thalassemic Disorders. Brigham and Women's Hospital and Harvard Medical School. Retrieved 2010-12-19.
December 15, 2023
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Transferrin receptor TfR is a carrier protein for transferrin It is needed for the import of iron into cells and is regulated in response to intracellular iron concentration It imports iron by internalizing the transferrin iron complex through receptor mediated endocytosis 1 The existence of a receptor for transferrin iron uptake has been recognized since the late 1950s 2 Earlier two transferrin receptors in humans transferrin receptor 1 and transferrin receptor 2 had been characterized and until recently cellular iron uptake was believed to occur 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 3 4 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 exists independent of these TfRs although the mechanisms are not well characterized 5 6 7 8 The multifunctional glycolytic enzyme glyceraldehyde 3 phosphate dehydrogenase GAPDH EC 1 2 1 12 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 9 10 11 Transferrin receptor 1Transferrin receptor 1 dimer HumanIdentifiersSymbolTFRCAlt symbolsCD71 TFR1NCBI gene7037HGNC11763OMIM190010RefSeqNM 003234UniProtP02786Other dataLocusChr 3 q29Search forStructuresSwiss modelDomainsInterProTransferrin receptor 2IdentifiersSymbolTFR2Alt symbolsHFE3 TFRC2NCBI gene7036HGNC11762OMIM604720RefSeqNM 003227UniProtQ9UP52Other dataLocusChr 7 q22Search forStructuresSwiss modelDomainsInterPro Contents 1 Post transcriptional regulation 2 See also 3 References 4 Further reading 5 External linksPost transcriptional regulation editLow 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 mRNA Once binding occurs the mRNA is stabilized and degradation is inhibited See also editTransferrin receptor 1 Transferrin receptor 2 Soluble transferrin receptor GAPDHReferences edit Qian ZM Li H Sun H Ho K December 2002 Targeted drug delivery via the transferrin receptor mediated endocytosis pathway Pharmacological Reviews 54 4 561 87 doi 10 1124 pr 54 4 561 PMID 12429868 S2CID 12453356 Figure 3 The cycle of transferrin and transferrin receptor 1 mediated cellular iron uptake Jandl JH Inman JK Simmons RL Allen DW January 1959 Transfer of iron from serum iron binding protein to human reticulocytes The Journal of Clinical Investigation 38 1 Part 1 161 85 doi 10 1172 JCI103786 PMC 444123 PMID 13620780 Kawabata H Germain RS Vuong PT Nakamaki T Said JW Koeffler HP June 2000 Transferrin receptor 2 alpha supports cell growth both in iron chelated cultured cells and in vivo The Journal of Biological Chemistry 275 22 16618 25 doi 10 1074 jbc M908846199 PMID 10748106 West AP Bennett MJ Sellers VM Andrews NC Enns CA Bjorkman PJ December 2000 Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE The Journal of Biological Chemistry 275 49 38135 8 doi 10 1074 jbc C000664200 PMID 11027676 Gkouvatsos K Papanikolaou G Pantopoulos K March 2012 Regulation of iron transport and the role of transferrin Biochimica et Biophysica Acta BBA General Subjects 1820 3 188 202 doi 10 1016 j bbagen 2011 10 013 PMID 22085723 Trinder D Zak O Aisen P June 1996 Transferrin receptor independent uptake of differic transferrin by human hepatoma cells with antisense inhibition of receptor expression Hepatology 23 6 1512 20 doi 10 1053 jhep 1996 v23 pm0008675172 PMID 8675172 Kozyraki R Fyfe J Verroust PJ Jacobsen C Dautry Varsat A Gburek J Willnow TE Christensen EI Moestrup SK October 2001 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 of the United States of America 98 22 12491 6 Bibcode 2001PNAS 9812491K doi 10 1073 pnas 211291398 PMC 60081 PMID 11606717 Yang J Goetz D Li JY Wang W Mori K Setlik D Du T Erdjument Bromage H Tempst P Strong R Barasch J November 2002 An iron delivery pathway mediated by a lipocalin Molecular Cell 10 5 1045 56 doi 10 1016 s1097 2765 02 00710 4 PMID 12453413 Sirover MA December 2014 Structural analysis of glyceraldehyde 3 phosphate dehydrogenase functional diversity The International Journal of Biochemistry amp Cell Biology 57 20 6 doi 10 1016 j biocel 2014 09 026 PMC 4268148 PMID 25286305 Boradia VM Raje M Raje CI December 2014 Protein moonlighting in iron metabolism glyceraldehyde 3 phosphate dehydrogenase GAPDH Biochemical Society Transactions 42 6 1796 801 doi 10 1042 BST20140220 PMID 25399609 Sheokand N Malhotra H Kumar S Tillu VA Chauhan AS Raje CI Raje M October 2014 Moonlighting cell surface GAPDH recruits apotransferrin to effect iron egress from mammalian cells PDF Journal of Cell Science 127 Pt 19 4279 91 doi 10 1242 jcs 154005 PMID 25074810 S2CID 9917899 Further reading editTesta U Kuhn 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 The Journal of Biological Chemistry 266 21 13925 30 doi 10 1016 S0021 9258 18 92790 0 PMID 1856222 Daniels TR Delgado T Rodriguez JA Helguera G Penichet ML November 2006 The transferrin receptor part I Biology and targeting with cytotoxic antibodies for the treatment of cancer Clinical Immunology 121 2 144 58 doi 10 1016 j clim 2006 06 010 PMID 16904380 Figure 3 Cellular uptake of iron through the Tf system via receptor mediated endocytosis Daniels TR Delgado T Helguera G Penichet ML November 2006 The transferrin receptor part II targeted delivery of therapeutic agents into cancer cells Clinical Immunology 121 2 159 76 doi 10 1016 j clim 2006 06 006 PMID 16920030 External links editTransferrin receptor at the U S National Library of Medicine Medical Subject Headings MeSH Okam M 2001 01 29 Iron Transport and Cellular Uptake Information Center for Sickle Cell and Thalassemic Disorders Brigham and Women s Hospital and Harvard Medical School Retrieved 2010 12 19 Retrieved from https en wikipedia org w index php title Transferrin receptor amp oldid 1182245922, wikipedia, wiki, book, books, library,
