The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body

Frontiers in Pharmacology

Volumn 5 MAR, Issue , 2014, Pages

  Worthen, Christal A ^a   Enns, Caroline A ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

Hepcidin; Hereditary hemochromatosis; Iron homeostasis; Liver; Transferrin receptor 2

Indexed keywords

BONE MORPHOGENETIC PROTEIN; HEPCIDIN; SMAD6 PROTEIN; SMAD7 PROTEIN; TRANSFERRIN; TRANSFERRIN RECEPTOR 2;

BINDING AFFINITY; BINDING SITE; BIOACCUMULATION; ENDOPLASMIC RETICULUM; GLYCOSYLATION; HOMEOSTASIS; HORMONAL REGULATION; HUMAN; METABOLIC REGULATION; PROMOTER REGION; PROTEIN BINDING; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FOLDING; PROTEIN METABOLISM; PROTEIN TRANSPORT; REVIEW; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; UPREGULATION;

EID: 84897930781     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2014.00034     Document Type: Review

References (96)

1. Abboud, S., and Haile, D. J. (2000). A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J. Biol. Chem. 275, 19906-19912. doi: 10.1074/jbc.M000713200.
2. Andrews, N. C. (1999). Disorders of iron metabolism. N. Engl. J. Med. 341, 1986-1995. doi: 10.1056/NEJM199912233412607.
3. Andriopoulos, B. Jr., Corradini, E., Xia, Y., Faasse, S. A., Chen, S., Grgurevic, L., et al. (2009). BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 41, 482-487. doi: 10.1038/ng.335.
4. Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., et al. (2006). Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531-539. doi: 10.1038/ng1777.
5. Bartnikas, T. B., Andrews, N. C., and Fleming, M. D. (2011). Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. Blood 117, 630-637. doi: 10.1182/blood-2010-05-287359.
6. Bartnikas, T. B., and Fleming, M. D. (2012). Hemojuvelin is essential for transferrin-dependent and transferrin-independent hepcidin expression in mice. Haematologica 97, 189-192. doi: 10.3324/haematol.2011.054031.
7. Bennett, M. J., Lebron, J. A., and Bjorkman, P. J. (2000). Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 403, 46-53. doi: 10.1038/47417.
8. Biasiotto, G., Camaschella, C., Forni, G. L., Polotti, A., Zecchina, G., and Arosio, P. (2008). New TFR2 mutations in young Italian patients with hemochromatosis. Haematologica 93, 309-310. doi: 10.3324/haematol.11942.
9. Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., et al. (2000). The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat. Genet. 25, 14-15. doi: 10.1038/75534.
10. Carlson, H., Zhang, A. S., Fleming, W. H., and Enns, C. A. (2005). The hereditary hemochromatosis protein, HFE, lowers intracellular iron levels independently of transferrin receptor 1 in TRVb cells. Blood 105, 2564-2570. doi: 10.1182/blood-2004-03-1204.
11. Casanovas, G., Mleczko-Sanecka, K., Altamura, S., Hentze, M. W., and Muckenthaler, M. U. (2009). Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J. Mol. Med. (Berl.) 87, 471-480. doi: 10.1007/s00109-009-0447-2.
12. Cecchetti, G., Binda, A., Piperno, A., Nador, F., Fargion, S., and Fiorelli, G. (1991). Cardiac alterations in 36 consecutive patients with idiopathic haemochromatosis: polygraphic and echocardiographic evaluation. Eur. Heart J. 12, 224-230.
13. Chen, J., Chloupkova, M., Gao, J., Chapman-Arvedson, T. L., and Enns, C. A. (2007). HFE modulates transferrin receptor 2 levels in hepatoma cells via interactions that differ from transferrin receptor 1-HFE interactions. J. Biol. Chem. 282, 36862-36870. doi: 10.1074/jbc.M706720200.
14. Chen, J., Wang, J., Meyers, K. R., and Enns, C. A. (2009). Transferrin-directed internalization and cycling of transferrin receptor 2. Traffic 10, 1488-1501. doi: 10.1111/j.1600-0854.2009.00961.x.
15. Cook, J. D., Barry, W. E., Hershko, C., Fillet, G., and Finch, C. A. (1973). Iron kinetics with emphasis on iron overload. Am. J. Pathol. 72, 337-344.
16. Corradini, E., Garuti, C., Montosi, G., Ventura, P., Andriopoulos, B. Jr., Lin, H. Y., et al. (2009). Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology 137, 1489-1497. doi: 10.1053/j.gastro.2009.06.057.
17. Corradini, E., Rozier, M., Meynard, D., Odhiambo, A., Lin, H. Y., Feng, Q., et al. (2011). Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe. Gastroenterology 141, 1907-1914. doi: 10.1053/j.gastro.2011.06.077.
18. D'Alessio, F., Hentze, M. W., and Muckenthaler, M. U. (2012). The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. J. Hepatol. 57, 1052-1060. doi: 10.1016/j.jhep.2012.06.015.
19. Dautry-Varsat, A., Ciechanover, A., and Lodish, H. F. (1983). pH and the recycling of transferrin during receptor-mediated endocytosis. Proc. Natl. Acad. Sci. U.S.A. 80, 2258-2262. doi: 10.1073/pnas.80.8.2258.
20. Donovan, A., Brownlie, A., Zhou, Y., Shepard, J., Pratt, S. J., Moynihan, J., et al. (2000). Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776-781. doi: 10.1038/35001596.
21. Enns, C. A., Ahmed, R., Wang, J., Ueno, A., Worthen, C., Tsukamoto, H., et al. (2013). Increased iron loading induces Bmp6 expression in the non-parenchymal cells of the liver independent of the BMP-signaling pathway. PLoS ONE 8:e60534. doi: 10.1371/journal.pone.0060534.
22. Fleming, R. E., Migas, M. C., Holden, C. C., Waheed, A., Britton, R. S., Tomatsu, S., et al. (2000). Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc. Natl. Acad. Sci. U.S.A. 97, 2214-2219. doi: 10.1073/pnas.040548097.
23. Gao, J., Chen, J., De Domenico, I., Koeller, D. M., Harding, C. O., Fleming, R. E., et al. (2010). Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 115, 3374-3381. doi: 10.1182/blood-2009-09-245209.
24. Gao, J., Chen, J., Kramer, M., Tsukamoto, H., Zhang, A. S., and Enns, C. A. (2009). Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. 9, 217-227. doi: 10.1016/j.cmet.2009.01.010.
25. Gerolami, V., Le Gac, G., Mercier, L., Nezri, M., Berge-Lefranc, J. L., and Ferec, C. (2008). Early-onset haemochromatosis caused by a novel combination of TFR2 mutations(p.R396X/c.1538-2 A > G) in a woman of Italian descent. Haematologica 93, e45-e46. doi: 10.3324/haematol.12884.
26. Giannetti, A. M., and Bjorkman, P. J. (2004). HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J. Biol. Chem. 279, 25866-25875. doi: 10.1074/jbc.M401467200.
27. Giannetti, A. M., Snow, P. M., Zak, O., and Bjorkman, P. J. (2003). Mechanism for multiple ligand recognition by the human transferrin receptor. PLoS Biol. 1:e51. doi: 10.1371/journal.pbio.0000051.
28. Girelli, D., Trombini, P., Busti, F., Campostrini, N., Sandri, M., Pelucchi, S., et al. (2011). A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis. Haematologica 96, 500-506. doi: 10.3324/haematol.2010.033449.
29. Goswami, T., and Andrews, N. C. (2006). Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J. Biol. Chem. 281, 28494-28498. doi: 10.1074/jbc.C600197200.
30. Gunshin, H., Mackenzie, B., Berger, U. V., Gunshin, Y., Romero, M. F., Boron, W. F., et al. (1997). Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482-488. doi: 10.1038/41343.
31. Hattori, A., Wakusawa, S., Hayashi, H., Harashima, A., Sanae, F., Kawanaka, M., et al. (2003). AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosis. Hepatol. Res. 26, 154-156. doi: 10.1016/S1386-6346(03)00086-X.
32. Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y. Y., Grinnell, B. W., et al. (1997). The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 89, 1165-1173. doi: 10.1016/S0092-8674(00)80303-7.
33. Hayashi, H., Wakusawa, S., Motonishi, S., Miyamoto, K., Okada, H., Inagaki, Y., et al. (2006). Genetic background of primary iron overload syndromes in Japan. Intern. Med. 45, 1107-1111. doi: 10.2169/internalmedicine.45.1876.
34. Hsiao, P. J., Tsai, K. B., Shin, S. J., Wang, C. L., Lee, S. T., Lee, J. F., et al. (2007). A novel mutation of transferrin receptor 2 in a Taiwanese woman with type 3 hemochromatosis. J. Hepatol. 47, 303-306. doi: 10.1016/j.jhep.2007.04.014.
35. Johnson, M. B., Chen, J., Murchison, N., Green, F. A., and Enns, C. A. (2007). Transferrin receptor 2: evidence for ligand-induced stabilization and redirection to a recycling pathway. Mol. Biol. Cell 18, 743-754. doi: 10.1091/mbc.E06-09-0798.
36. Johnson, M. B., and Enns, C. A. (2004). Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 104, 4287-4293. doi: 10.1182/blood-2004-06-2477.
37. Kautz, L., Meynard, D., Monnier, A., Darnaud, V., Bouvet, R., Wang, R. H., et al. (2008). Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112, 1503-1509. doi: 10.1182/blood-2008-03-143354.
38. Kavsak, P., Rasmussen, R. K., Causing, C. G., Bonni, S., Zhu, H., Thomsen, G. H., et al. (2000). Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol. Cell 6, 1365-1375. doi: 10.1016/S1097-2765(00)00134-9.
39. Kawabata, H., Fleming, R. E., Gui, D., Moon, S. Y., Saitoh, T., O'kelly, J., et al. (2005). Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 105, 376-381. doi: 10.1182/blood-2004-04-1416.
40. Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., et al. (1999). Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J. Biol. Chem. 274, 20826-20832. doi: 10.1074/jbc.274.30.20826.
41. Kemna, E. H., Tjalsma, H., Willems, H. L., and Swinkels, D. W. (2008). Hepcidin: from discovery to differential diagnosis. Haematologica 93, 90-97. doi: 10.3324/haematol.11705.
42. Knittel, T., Fellmer, P., Muller, L., and Ramadori, G. (1997). Bone morphogenetic protein-6 is expressed in nonparenchymal liver cells and upregulated by transforming growth factor-beta 1. Exp. Cell Res. 232, 263-269. doi: 10.1006/excr.1997.3504.
43. Koorts, A. M., and Viljoen, M. (2007). Ferritin and ferritin isoforms I: structure-function relationships, synthesis, degradation and secretion. Arch. Physiol. Biochem. 113, 30-54. doi: 10.1080/13813450701318583.
44. Koyama, C., Wakusawa, S., Hayashi, H., Suzuki, R., Yano, M., Yoshioka, K., et al. (2005). Two novel mutations, L490R and V561X, of the transferrin receptor 2 gene in Japanese patients with hemochromatosis. Haematologica 90, 302-307.
45. Lagna, G., Hata, A., Hemmati-Brivanlou, A., and Massague, J. (1996). Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Nature 383, 832-836. doi: 10.1038/383832a0.
46. Le Gac, G., Mons, F., Jacolot, S., Scotet, V., Ferec, C., and Frebourg, T. (2004). Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. Br. J. Haematol. 125, 674-678. doi: 10.1111/j.1365-2141.2004.04950.x.
47. Levy, J. E., Jin, O., Fujiwara, Y., Kuo, F., and Andrews, N. C. (1999). Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat. Genet. 21, 396-399. doi: 10.1038/7727.
48. Lin, L., Valore, E. V., Nemeth, E., Goodnough, J. B., Gabayan, V., and Ganz, T. (2007). Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 110, 2182-2189. doi: 10.1182/blood-2007-04-087593.
49. Liu, X. B., Nguyen, N. B., Marquess, K. D., Yang, F., and Haile, D. J. (2005). Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages. Blood Cells Mol. Dis. 35, 47-56. doi: 10.1016/j.bcmd.2005.04.006.
50. Macias-Silva, M., Abdollah, S., Hoodless, P. A., Pirone, R., Attisano, L., and Wrana, J. L. (1996). MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell 87, 1215-1224. doi: 10.1016/S0092-8674(00)81817-6.
51. Majore, S., Milano, F., Binni, F., Stuppia, L., Cerrone, A., Tafuri, A., et al. (2006). Homozygous p.M172K mutation of the TFR2 gene in an Italian family with type 3 hereditary hemochromatosis and early onset iron overload. Haematologica 91, ECR33.
52. Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., et al. (2002). Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Blood 100, 1075-1077. doi: 10.1182/blood-2002-01-0133.
53. McKie, A. T., Barrow, D., Latunde-Dada, Go., Rolfs, A., Sager, G., Mudaly, E., et al. (2001). An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755-1759. doi: 10.1126/science.1057206.
54. McKie, A. T., Marciani, P., Rolfs, A., Brennan, K., Wehr, K., Barrow, D., et al. (2000). A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell 5, 299-309. doi: 10.1016/S1097-2765(00)80425-6.
55. Meynard, D., Kautz, L., Darnaud, V., Canonne-Hergaux, F., Coppin, H., and Roth, M. P. (2009). Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat. Genet. 41, 478-481. doi: 10.1038/ng.320.
56. Mleczko-Sanecka, K., Casanovas, G., Ragab, A., Breitkopf, K., Muller, A., Boutros, M., et al. (2010). SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood 115, 2657-2665. doi: 10.1182/blood-2009-09-238105.
57. Nemeth, E., Roetto, A., Garozzo, G., Ganz, T., and Camaschella, C. (2005). Hepcidin is decreased in TFR2 hemochromatosis. Blood 105, 1803-1806. doi: 10.1182/blood-2004-08-3042.
58. Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., et al. (2004). Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090-2093. doi: 10.1126/science.1104742.
59. Owen, D., and Kuhn, L. C. (1987). Noncoding 3' sequences of the transferrin receptor gene are required for mRNA regulation by iron. EMBO J. 6, 1287-1293.
60. Peyssonnaux, C., Zinkernagel, A. S., Datta, V., Lauth, X., Johnson, R. S., and Nizet, V. (2006). TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood 107, 3727-3732. doi: 10.1182/blood-2005-06-2259.
61. Pietrangelo, A., Caleffi, A., Henrion, J., Ferrara, F., Corradini, E., Kulaksiz, H., et al. (2005). Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 128, 470-479. doi: 10.1053/j.gastro.2004.11.057.
62. Radio, F. C., Majore, S., Binni, F., Valiante, M., Ricerca, B. M., De Bernardo, C., et al. (2014). TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy. Blood Cells Mol. Dis. 52, 83-87. doi: 10.1016/j.bcmd.2013.08.003.
63. Ramey, G., Deschemin, J. C., and Vaulont, S. (2009). Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica 94, 765-772. doi: 10.3324/haematol.2008.003541.
64. Ramos, E., Kautz, L., Rodriguez, R., Hansen, M., Gabayan, V., Ginzburg, Y., et al. (2011). Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology 53, 1333-1341. doi: 10.1002/hep.24178.
65. Rao, K., Van Renswoude, J., Kempf, C., and Klausner, R. D. (1983). Separation of Fe+3 from transferrin in endocytosis. Role of the acidic endosome. FEBS Lett. 160, 213-216. doi: 10.1016/0014-5793(83)80969-7.
66. Robb, A., and Wessling-Resnick, M. (2004). Regulation of transferrin receptor 2 protein levels by transferrin. Blood 104, 4294-4299. doi: 10.1182/blood-2004-06-2481.
67. Roetto, A., Di Cunto, F., Pellegrino, R. M., Hirsch, E., Azzolino, O., Bondi, A., et al. (2010). Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-alpha and Tfr2-beta isoforms in different tissues. Blood 115, 3382-3389. doi: 10.1182/blood-2009-09-240960.
68. Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., et al. (2001). New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 97, 2555-2560. doi: 10.1182/blood.V97.9.2555.
69. Roy, C. N., Penny, D. M., Feder, J. N., and Enns, C. A. (1999). The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J. Biol. Chem. 274, 9022-9028. doi: 10.1074/jbc.274.13.9022.
70. Schmidt, P. J., and Fleming, M. D. (2012). Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2. Am. J. Hematol. 87, 588-595. doi: 10.1002/ajh.23173.
71. Schumacher, H. R. Jr. (1964). Hemochromatosis and arthritis. Arthritis Rheum. 7, 41-50. doi: 10.1002/art.1780070106.
72. Solloway, M. J., Dudley, A. T., Bikoff, E. K., Lyons, K. M., Hogan, B. L., and Robertson, E. J. (1998). Mice lacking Bmp6 function. Dev. Genet. 22, 321-339. doi: 10.1002/(sici)1520-6408(1998)22:4 < 321::aid-dvg3 > 3.0.co;2-8.
73. Souchelnytskyi, S., Ten Dijke, P., Miyazono, K., and Heldin, C. H. (1996). Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses. EMBO J. 15, 6231-6240.
74. Sposi, N. M., Cianetti, L., Tritarelli, E., Pelosi, E., Militi, S., Barberi, T., et al. (2000). Mechanisms of differential transferrin receptor expression in normal hematopoiesis. Eur. J. Biochem. 267, 6762-6774. doi: 10.1046/j.1432-1033.2000.01769.x.
75. Steinbicker, A. U., Bartnikas, T. B., Lohmeyer, L. K., Leyton, P., Mayeur, C., Kao, S. M., et al. (2011). Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood 118, 4224-4230. doi: 10.1182/blood-2011-03-339952.
76. Trenor, C. C. III, Campagna, D. R., Sellers, V. M., Andrews, N. C., and Fleming, M. D. (2000). The molecular defect in hypotransferrinemic mice. Blood 96, 1113-1118.
77. Truksa, J., Lee, P., and Beutler, E. (2009). Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness. Blood 113, 688-695. doi: 10.1182/blood-2008-05-160184.
78. Truksa, J., Lee, P., Peng, H., Flanagan, J., and Beutler, E. (2007). The distal location of the iron responsive region of the hepcidin promoter. Blood 110, 3436-3437. doi: 10.1182/blood-2007-05-091108.
79. Valore, E. V., and Ganz, T. (2008). Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol. Dis. 40, 132-138. doi: 10.1016/j.bcmd.2007.07.009.
80. Van Dijk, B. A., Laarakkers, C. M., Klaver, S. M., Jacobs, E. M., Van Tits, L. J., Janssen, M. C., et al. (2008). Serum hepcidin levels are innately low in HFE-related haemochromatosis but differ between C282Y-homozygotes with elevated and normal ferritin levels. Br. J. Haematol. 142, 979-985. doi: 10.1111/j.1365-2141.2008.07273.x.
81. Verga Falzacappa, M. V., Casanovas, G., Hentze, M. W., and Muckenthaler, M. U. (2008). A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J. Mol. Med. (Berl.) 86, 531-540. doi: 10.1007/s00109-008-0313-7.
82. Vujic Spasic, M., Sparla, R., Mleczko-Sanecka, K., Migas, M. C., Breitkopf-Heinlein, K., Dooley, S., et al. (2013). Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. Biochim. Biophys. Acta 1832, 76-84. doi: 10.1016/j.bbadis.2012.08.013.
83. Vulpe, C. D., Kuo, Y. M., Murphy, T. L., Cowley, L., Askwith, C., Libina, N., et al. (1999). Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat. Genet. 21, 195-199. doi: 10.1038/5979.
84. Wallace, D. F., Summerville, L., Crampton, E. M., Frazer, D. M., Anderson, G. J., and Subramaniam, V. N. (2009). Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology 50, 1992-2000. doi: 10.1002/hep.23198.
85. Wallace, D. F., Summerville, L., Crampton, E. M., and Subramaniam, V. N. (2008). Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis. Am. J. Physiol. Cell Physiol. 294, C383-C390. doi: 10.1152/ajpcell.00492.2007.
86. Wang, J., Chen, G., and Pantopoulos, K. (2003). The haemochromatosis protein HFE induces an apparent iron-deficient phenotype in H1299 cells that is not corrected by co-expression of beta 2-microglobulin. Biochem. J. 370, 891-899. doi: 10.1042/bj20021607.
87. Wang, R. H., Li, C., Xu, X., Zheng, Y., Xiao, C., Zerfas, P., et al. (2005). A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2, 399-409. doi: 10.1016/j.cmet.2005.10.010.
88. Weber, F. P. (1931). Haemochromatosis, with Diabetes Mellitus, Hepatic Cirrhosis and Chronic Ascites. Proc. R. Soc. Med. 24, 478.
89. West, A. P. Jr., Bennett, M. J., Sellers, V. M., Andrews, N. C., Enns, C. A., and Bjorkman, P. J. (2000). Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. J. Biol. Chem. 275, 38135-38138. doi: 10.1074/jbc.C000664200.
90. Wrana, J. L., Attisano, L., Carcamo, J., Zentella, A., Doody, J., Laiho, M., et al. (1992). TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71, 1003-1014 doi: 10.1016/0092-8674(92)90395-S.
91. Xia, Y., Babitt, J. L., Sidis, Y., Chung, R. T., and Lin, H. Y. (2008). Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 111, 5195-5204. doi: 10.1182/blood-2007-09-111567.
92. Zamani, F., Bagheri, Z., Bayat, M., Fereshtehnejad, S. M., Basi, A., Najmabadi, H., et al. (2012). Iranian hereditary hemochromatosis patients: baseline characteristics, laboratory data and gene mutations. Med. Sci. Monit. 18, CR622-CR629. doi: 10.12659/MSM.883489.
93. Zhang, A. S., Anderson, S. A., Wang, J., Yang, F., Demaster, K., Ahmed, R., et al. (2011). Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein. Blood 117, 1687-1699. doi: 10.1182/blood-2010-06-287292.
94. Zhang, S., Fei, T., Zhang, L., Zhang, R., Chen, F., Ning, Y., et al. (2007). Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol. Cell. Biol. 27, 4488-4499. doi: 10.1128/mcb.01636-06.
95. Zhao, N., and Enns, C. A. (2013). N-linked glycosylation is required for transferrin-induced stabilization of transferrin receptor 2, but not for transferrin binding or trafficking to the cell surface. Biochemistry 52, 3310-3319. doi: 10.1021/bi4000063.
96. Zhao, N., Gao, J., Enns, C. A., and Knutson, M. D. (2010). ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J. Biol. Chem. 285, 32141-32150. doi: 10.1074/jbc.M110.143248.