Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing.
Open accessAbstract
HFE and transferrin receptor 2 (TFR2) are membrane proteins integral to mammalian iron homeostasis and associated with human hereditary hemochromatosis. Here we demonstrate that HFE and TFR2 interact in cells, that this interaction is not abrogated by disease-associated mutations of HFE and TFR2, and that TFR2 competes with TFR1 for binding to HFE. We propose a new model for the mechanism of iron status sensing that results in the regulation of iron homeostasis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The authors have proposed a model in which TFR2 escorts HFE away from TFR1 when the serum iron level, reflected in transferrin saturation, is elevated.
“Taking this into account, we have proposed a model in which TFR2 escorts HFE away from TFR1 when the serum iron level (reflected in the transferrin saturation) is elevated.149,150”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [150]
TFR2 interacts with HFE to form a stable protein complex.
“Like TFR1, TFR2 interacts with HFE to form a stable protein complex.150”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [150]
Cites
Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., & Kaplan, J. (2004) · Science · doi:10.1126/science.1104742 · Cited by 4,803 · see citing works
Hentze, M. W., Muckenthaler, M. U., & Andrews, N. C. (2004) · Cell · doi:10.1016/s0092-8674(04)00343-5 · Cited by 1,736 · see citing works
Nicolas, G., Chauvet, C., Viatte, L., Danan, J. L., Bigard, X., Devaux, I., Beaumont, C., Kahn, A., & Vaulont, S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215686 · Cited by 1,214 · see citing works
Molecular Cloning of Transferrin Receptor 2
Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., & Koeffler, H. P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.30.20826 · Cited by 646 · see citing works
Weinstein, D. A., Roy, C. N., Fleming, M. D., Loda, M. F., Wolfsdorf, J. I., & Andrews, N. C. (2002) · Blood · doi:10.1182/blood-2002-04-1260 · Cited by 632 · see citing works
Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor
Bennett, M. J., Lebrón, J. A., & Björkman, P. J. (2000) · Nature · doi:10.1038/47417 · Cited by 338 · see citing works
Wu, J. C., Merlino, G. T., & Fausto, N. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.2.674 · Cited by 317 · see citing works
The C282Y Mutation Causing Hereditary Hemochromatosis Does Not Produce a Null Allele
Levy, J. E., Montross, L. K., Cohen, D. E., Fleming, M. D., & Andrews, N. C. (1999) · Blood · doi:10.1182/blood.v94.1.9.413a43_9_11 · Cited by 259 · see citing works
West, A. P., Bennett, M. J., Sellers, V. M., Andrews, N. C., Enns, C. A., & Bjorkman, P. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000664200 · Cited by 257 · see citing works
Diferric transferrin regulates transferrin receptor 2 protein stability
Johnson, M. B., & Enns, C. A. (2004) · Blood · doi:10.1182/blood-2004-06-2477 · Cited by 230 · see citing works
Sidis, Y., Mukherjee, A., Keutmann, H., Delbaere, A., Sadatsuki, M., & Schneyer, A. (2006) · Endocrinology · doi:10.1210/en.2006-0089 · Cited by 211 · see citing works
Regulation of transferrin receptor 2 protein levels by transferrin
Robb, A., & Wessling‐Resnick, M. (2004) · Blood · doi:10.1182/blood-2004-06-2481 · Cited by 204 · see citing works
McGraw, T. E., Greenfield, L., & Maxfield, F. R. (1987) · The Journal of Cell Biology · doi:10.1083/jcb.105.1.207 · Cited by 203 · see citing works
West, A. P., Giannetti, A. M., Herr, A. B., Bennett, M. J., Nangiana, J. S., Pierce, J. R., Weiner, L. P., Snow, P. M., & Björkman, P. J. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2001.5048 · Cited by 125 · see citing works
The molecular genetics of haemochromatosis
Gac, G. L., & Férec, C. (2005) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201490 · Cited by 85 · see citing works
Wilkins, S. J., Frazer, D. M., Millard, K. N., McLaren, G. D., & Anderson, G. J. (2005) · Blood · doi:10.1182/blood-2005-07-2614 · Cited by 56 · see citing works
Hemochromatosis Due to Mutations in Transferrin Receptor 2
Roetto, A., Daraio, F., Alberti, F., Porporato, P. E., Calı̀, A., Gobbi, M. D., & Camaschella, C. (2002) · Blood Cells Molecules and Diseases · doi:10.1006/bcmd.2002.0585 · Cited by 52 · see citing works
Griffiths, W. J., & Cox, T. M. (2003) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215540305100507 · Cited by 52 · see citing works
Regulation of ferritin and transferrin receptor expression by iron in human hepatocyte cultures
Hubert, N., Lescoat, G., Sciot, R., Moirand, R., Jégo, P., Leroyer, P., & Brissot, P. (1993) · Journal of Hepatology · doi:10.1016/s0168-8278(05)80274-0 · Cited by 41 · see citing works
Flagged first, then by citations
1 of the 20 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Two to tango: Regulation of Mammalian iron metabolism
Hentze, M. W., Muckenthaler, M. U., Galy, B., & Camaschella, C. (2010) · Cell · doi:10.1016/j.cell.2010.06.028 · Cited by 2,120 · see citing works
Ganz, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00008.2013 · Cited by 1,122 · see citing works
Muckenthaler, M. U., Galy, B., & Hentze, M. W. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155521 · Cited by 701 · see citing works
Bacon, B. R., Adams, P. C., Kowdley, K. V., Powell, L. W., & Tavill, A. S. (2011) · Hepatology · doi:10.1002/hep.24330 · Cited by 721 · see citing works
“HFE can bind to both TfR2 and to the classic transferrin receptor TfR1.(23,30) In addition, both HFE and TfR2 may interact with HJV, suggesting that a complex of HFE and TfR2 may play a regulatory role in BMP6 signaling.”
Transferrin and transferrin receptors update
Kawabata, H. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.06.037 · Cited by 697 · see citing works
Forging a field: the golden age of iron biology.
Andrews, N. C. (2008) · Blood · doi:10.1182/blood-2007-12-077388 · Cited by 623 · see citing works
Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment
Pietrangelo, A. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.06.013 · Cited by 615 · see citing works
The Role of Hepcidin in Iron Metabolism
Nemeth, E., & Ganz, T. (2009) · Acta Haematologica · doi:10.1159/000243791 · Cited by 607 · see citing works
“HFE, a protein similar to MHC class I molecules, does not bind iron directly but instead interacts with iron-binding proteins, TfR1 and TfR2. It has been proposed that HFE shuttles between TfR1 and TfR2 depending on iron Tf concentrations [”
BackgroundMechanisms of mammalian iron homeostasis
Pantopoulos, K., Porwal, S. K., Tartakoff, A., & Devireddy, L. (2012) · Biochemistry · doi:10.1021/bi300752r · Cited by 598 · see citing works
Iron Overload in Human Disease
Fleming, R. E., & Ponka, P. (2012) · New England Journal of Medicine · doi:10.1056/nejmra1004967 · Cited by 592 · see citing works
Regulation of iron transport and the role of transferrin
Gkouvatsos, K., Papanikolaou, G., & Pantopoulos, K. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.10.013 · Cited by 518 · see citing works
“of the holo-Tf levels [209].”
Brissot, P., Pietrangelo, A., Adams, P. C., de Graaff, B., McLaren, C. E., & Loréal, O. (2018) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2018.16 · Cited by 430 · see citing works
Oxidative Stress and Iron Homeostasis: Mechanistic and Health Aspects
Galaris, D., & Pantopoulos, K. (2008) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360701713104 · Cited by 352 · see citing works
Nelson, J. E., Wilson, L., Brunt, E. M., Yeh, M. M., Kleiner, D. E., Ünalp–Arida, A., & Kowdley, K. V. (2010) · Hepatology · doi:10.1002/hep.24038 · Cited by 354 · see citing works
“04 Insulin (lU/mL) 19 (13-29) 16 (11-24) 23 (12-32) 18 (12-23) 0.”
The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression
Schmidt, P. J., Toran, P. T., Giannetti, A. M., Bjorkman, P. J., & Andrews, N. C. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.11.016 · Cited by 345 · see citing works
Self-citationGao, J., Chen, J., Kramer, M., Tsukamoto, H., Zhang, A.-S., & Enns, C. A. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.01.010 · Cited by 326 · see citing works
“They speculate that the binding partner was TfR2 based on previous evidence showing that HFE is capable of binding to TfR2 (Chen et al., 2007; Goswami and Andrews, 2006).”
BackgroundHepcidin: from discovery to differential diagnosis
Kemna, E., Tjalsma, H., Willems, H. L., & Swinkels, D. W. (2007) · Haematologica · doi:10.3324/haematol.11705 · Cited by 313 · see citing works
Gardenghi, S., Marongiu, M. F., Ramos, P., Guy, E. C., Breda, L., Chadburn, A., Liu, Y.-F., Amariglio, N., Rechavi, G., Rachmilewitz, E. A., et al. (2007) · Blood · doi:10.1182/blood-2006-09-048868 · Cited by 307 · see citing works
Evstatiev, R., & Gasché, C. (2011) · Gut · doi:10.1136/gut.2010.214312 · Cited by 292 · see citing works
“Conversely, when iron-transferrin is high, HFE shuttles to TfR2 instead.(107) This TfR2eHFE interaction ultimately leads to hepcidin induction.”
BackgroundAthletic induced iron deficiency: new insights into the role of inflammation, cytokines and hormones
Peeling, P., Dawson, B., Goodman, C., Landers, G., & Trinder, D. (2008) · European Journal of Applied Physiology · doi:10.1007/s00421-008-0726-6 · Cited by 292 · see citing works
“For instance, hemochromatosis patients suffer a chronic mal-accumulation of iron within various tissues of the body (Goswami and Andrews 2006).”
BackgroundNew insights into iron deficiency and iron deficiency anemia
Camaschella, C. (2017) · Blood Reviews · doi:10.1016/j.blre.2017.02.004 · Cited by 278 · see citing works
Crux, N. B., & Elahi, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00832 · Cited by 243 · see citing works
“HFE is expressed strongly with the TfR2 on Kupffer cells, circulating monocytes and macrophages, as well as duodenal epithelial cells (280).”
BackgroundMolecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD
Babitt, J. L., & Lin, H. Y.-F. (2010) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2009.12.030 · Cited by 236 · see citing works
The Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 234 · see citing works
The role of iron homeostasis in remodeling immune function and regulating inflammatory disease
Mu, Q., Chen, L., Gao, X., Shen, S., Sheng, W., Min, J., & Wang, F. (2021) · 中国科学通报：英文版 · doi:10.1016/j.scib.2021.02.010 · Cited by 226 · see citing works
Hepcidin: regulation of the master iron regulator
Rishi, G., Wallace, D. F., & Subramaniam, V. N. (2015) · Bioscience Reports · doi:10.1042/bsr20150014 · Cited by 223 · see citing works
Hemochromatosis: An endocrine liver disease
Pietrangelo, A. (2007) · Hepatology · doi:10.1002/hep.21886 · Cited by 212 · see citing works
Lawen, A., & Lane, D. J. R. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4271 · Cited by 217 · see citing works
“Importantly, HFE can also bind to TfR2 (129), and HFE that is competitively displaced from TfR1 by holo-Tf then becomes available to interact with TfR2, the latter of which is expressed highly in the liver (61).”
Zhao, N., Zhang, A., & Enns, C. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67225 · Cited by 210 · see citing works
“HFE interacts with TfR2 (40, 41) and both are predominantly expressed in hepatocytes (42).”
Wallace, D. F., Summerville, L., Crampton, E. M., Frazer, D. M., Anderson, G. J., & Subramaniam, V. N. (2009) · Hepatology · doi:10.1002/hep.23198 · Cited by 206 · see citing works
D’Alessio, F., Hentze, M. W., & Muckenthaler, M. U. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.06.015 · Cited by 200 · see citing works
“To confirm that the conditions of the immunoprecipitation assay mirror the physiological competition between TfR1 and TfR2 for HFE [16], we co-expressed increasing amounts of either TfR2HA or Flag-HFE, together with a constant amount of Flag-HFE or TfR2-HA, respectively.”
BackgroundMethodGinzburg, Y., & Rivella, S. (2011) · Blood · doi:10.1182/blood-2011-03-283614 · Cited by 201 · see citing works
Hepcidin Regulation of Iron Transport
Collins, J. F., Wessling‐Resnick, M., & Knutson, M. D. (2008) · Journal of Nutrition · doi:10.3945/jn.108.096347 · Cited by 199 · see citing works
“However, in vitro studies showing that HFE and TfR2 interact suggest that these 2 molecules work together to sense iron (15,16).”
BackgroundThe Role of Iron in the Immune Response to Bacterial Infection
Cherayil, B. J. (2011) · Immunologic Research · doi:10.1007/s12026-010-8199-1 · Cited by 191 · see citing works
Out of Balance—Systemic Iron Homeostasis in Iron-Related Disorders
Steinbicker, A. U., & Muckenthaler, M. U. (2013) · Nutrients · doi:10.3390/nu5083034 · Cited by 196 · see citing works
“Transferrin receptor 2 TFR2 Receptor for iron-bound transferring, possibly involved in iron sensing by interacting with HFE [76,77].”
BackgroundInfluentialIron homeostasis: An anthropocentric perspective
Coffey, R., & Ganz, T. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.781823 · Cited by 189 · see citing works
“Holotransferrin binds to transferrin receptors (TFR) 1 and 2, respectively for cellular iron acquisition (61) and iron-sensing by the liver (41).”
BackgroundInfluentialIron regulation and erythropoiesis
Nemeth, E. (2008) · Current Opinion in Hematology · doi:10.1097/moh.0b013e3282f73335 · Cited by 175 · see citing works
Graham, R. M. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i35.4725 · Cited by 180 · see citing works
The liver: conductor of systemic iron balance
Meynard, D., Babitt, J. L., & Lin, H. Y.-F. (2013) · Blood · doi:10.1182/blood-2013-06-427757 · Cited by 178 · see citing works
Regulation of Hepcidin and Iron-Overload Disease
Lee, P. L., & Beutler, E. (2009) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092205 · Cited by 174 · see citing works
Iron uptake and transport across physiological barriers
Duck, K. A., & Connor, J. R. (2016) · BioMetals · doi:10.1007/s10534-016-9952-2 · Cited by 176 · see citing works
The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders
Ganz, T., & Nemeth, E. (2011) · Hematology · doi:10.1182/asheducation-2011.1.538 · Cited by 172 · see citing works
Hepcidin regulation: ironing out the details
Domenico, I. D., Ward, D. M., & Kaplan, J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32701 · Cited by 171 · see citing works
Iron refractory iron deficiency anemia
Falco, L. D., Sánchez, M., Silvestri, L., Kannengiesser, C., Muckenthaler, M. U., Iolascon, A., Gouya, L., Camaschella, C., & Beaumont, C. (2013) · Haematologica · doi:10.3324/haematol.2012.075515 · Cited by 182 · see citing works
Iron and Immunity: Immunological Consequences of Iron Deficiency and Overload
Cherayil, B. J. (2010) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-010-0095-9 · Cited by 170 · see citing works
“The latter interaction activates signals that induce the transcriptional up-regulation of hepcidin (Goswami and Andrews 2006; Schmidt et al. 2008).”
The Regulation of Cellular Iron Metabolism
Chua, A. C. G., Graham, R. M., Trinder, D., & Olynyk, J. K. (2007) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360701428257 · Cited by 168 · see citing works
Crossing the Iron Gate: Why and How Transferrin Receptors Mediate Viral Entry
Wessling‐Resnick, M. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-082117-051749 · Cited by 163 · see citing works
“Ultimately, increasing iron saturation of Tf confers a signal to upregulate hepcidin synthesis (70).”
BackgroundSelective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice
Wang, L., Harrington, L., Trebicka, E., Shi, H. N., Kagan, J. C., Hong, C. C., Lin, H. Y., Babitt, J. L., & Cherayil, B. J. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39939 · Cited by 162 · see citing works
Wang, L., Johnson, E. E., Shi, H. N., Walker, W. A., Wessling-Resnick, M., & Cherayil, B. J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2723 · Cited by 159 · see citing works
Hepcidin-ferroportin axis in health and disease
Ginzburg, Y. Z. (2019) · Vitamins and hormones · doi:10.1016/bs.vh.2019.01.002 · Cited by 165 · see citing works
Iron Homeostasis: Recently Identified Proteins Provide Insight into Novel Control Mechanisms
Zhang, A.-S., & Enns, C. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.r800017200 · Cited by 153 · see citing works
Hfe Acts in Hepatocytes to Prevent Hemochromatosis
Spasić, M. V., Kiss, J., Herrmann, T. R. W., Galy, B., Martinache, S., Stolte, J., Gröne, H., Stremmel, W., Hentze, M. W., & Muckenthaler, M. U. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.11.014 · Cited by 150 · see citing works
Molecular mechanisms of normal iron homeostasis
Zhang, A.-S., & Enns, C. A. (2009) · Hematology · doi:10.1182/asheducation-2009.1.207 · Cited by 145 · see citing works
“TfR2 also interacts with HFE in transfected mammalian cells.(15) The co-crystal structure of the ectodomains of HFE and TfR1 indicates that the α1- and α2-helices in HFE interact with the helical domain of TfR1.”
BackgroundThe pathophysiology and pharmacology of hepcidin
Ruchala, P. P., & Nemeth, E. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.01.004 · Cited by 140 · see citing works
“HFE, TfR2 and HJV mutations were also described in humans and result in hepcidin levels that are inappropriately low for the degree of iron overload observed in these patients [21–23].”
BackgroundInfluentialBone Morphogenetic Protein Signaling Is Impaired in an Hfe Knockout Mouse Model of Hemochromatosis
Corradini, E., Garuti, C., Montosi, G., Ventura, P., Andriopoulos, B., Lin, H. Y.-F., Pietrangelo, A., & Babitt, J. L. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.06.057 · Cited by 140 · see citing works
Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin
Pietrangelo, A. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.06.045 · Cited by 136 · see citing works
Viatte, L., & Vaulont, S. (2009) · Biochimie · doi:10.1016/j.biochi.2009.06.012 · Cited by 134 · see citing works
The Regulation of Hepcidin and Its Effects on Systemic and Cellular Iron Metabolism
Fleming, M. D. (2008) · Hematology · doi:10.1182/asheducation-2008.1.151 · Cited by 131 · see citing works
HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression
Wu, X.-G., Wang, Y., Wu, Q., Cheng, W. H., Liu, W., Zhao, Y., Mayeur, C., Schmidt, P. J., Yu, P. B., Wang, F., et al. (2014) · Blood · doi:10.1182/blood-2014-01-552281 · Cited by 129 · see citing works
Current approach to hemochromatosis
Brissot, P., Troadec, M., Bardou‐Jacquet, E., Lan, C. L., Jouanolle, A., Deugnier, Y., & Loréal, O. (2008) · Blood Reviews · doi:10.1016/j.blre.2008.03.001 · Cited by 129 · see citing works
“The mechanisms likely involve physical interactions between HFE, TfR2, and TfR1.”
BackgroundThe Liver in Regulation of Iron Homeostasis
Rishi, G., & Subramaniam, V. N. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00004.2017 · Cited by 124 · see citing works
“The current theory is that in conditions of increased body iron levels, TFR1 binds to saturated transferrin and is internalized, thus releasing HFE (8, 25, 29).”
BackgroundManipulation of the hepcidin pathway for therapeutic purposes
Fung, E., & Nemeth, E. (2013) · Haematologica · doi:10.3324/haematol.2013.084624 · Cited by 124 · see citing works
Ramey, G., Deschemin, J., & Vaulont, S. (2009) · Haematologica · doi:10.3324/haematol.2008.003541 · Cited by 122 · see citing works
“Key words: hepcidin, iron, hepatocyte, ERK1/2, BMP/HJV, HFE, TfR2.”
BackgroundInfluentialUrrutia, P. J., Bórquez, D. A., & Núñez, M. T. (2021) · Antioxidants · doi:10.3390/antiox10010061 · Cited by 125 · see citing works
Iron Metabolism in Nonalcoholic Fatty Liver Disease
Nelson, J. E., Klintworth, H. M., & Kowdley, K. V. (2011) · Current Gastroenterology Reports · doi:10.1007/s11894-011-0234-4 · Cited by 119 · see citing works
“Positive regulation of hepcidin occurs in response to elevated body iron stores via the BMP/HJV/SMAD pathway [23] and in sensing plasma transferrin levels through the HFE/TFR1/TFR2 complex [24–26].”
Iron Homeostasis: Fitting the Puzzle Pieces Together
Ganz, T. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.03.008 · Cited by 120 · see citing works
“HFE and TfR2 also interact (Goswami and Andrews, 2006; Chen et al., 2007), but unlike the TfR1-HFE interaction, there is no competition by holotransferrin.”
BackgroundRegulation of hepcidin: Insights from biochemical analyses on human serum samples
Kemna, E., Kartikasari, A. E. R., van Tits, L. J. H., Pickkers, P., Tjalsma, H., & Swinkels, D. W. (2007) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2007.10.002 · Cited by 116 · see citing works
Hepcidin in human iron disorders: Therapeutic implications
Pietrangelo, A. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.08.004 · Cited by 115 · see citing works
“Another possibility is that TfR2, which is also able to interact with HFE [60–63], forms an ironsensing complex that modulates hepcidin expression in response to blood levels of diferric transferrin [61,64].”
Hepcidin modulation in human diseases: From research to clinic
Piperno, A., Mariani, R., Trombini, P., & Girelli, D. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.538 · Cited by 115 · see citing works
Young, B. Y., & Zaritsky, J. J. (2009) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.02190309 · Cited by 114 · see citing works
“acts with transferrin receptors 1 and 2, likely linking the sensing of serum iron with hepcidin production (14,15).”
BackgroundA fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates
Cooke, K. S., Hinkle, B., Salimi-Moosavi, H., Foltz, I., King, C., Rathanaswami, P., Winters, A., Steavenson, S., Begley, C. G., Molineux, G., et al. (2013) · Blood · doi:10.1182/blood-2013-06-505792 · Cited by 113 · see citing works
Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms
Kleven, M. D., Jue, S. F., & Enns, C. A. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00006 · Cited by 112 · see citing works
BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression
Kautz, L., Meynard, D., Besson‐Fournier, C., Darnaud, V., Saati, T. A., Coppin, H., & Roth, M. (2009) · Blood · doi:10.1182/blood-2009-02-206771 · Cited by 110 · see citing works
Corradini, E., Schmidt, P. J., Meynard, D., Garuti, C., Montosi, G., Chen, S., Vukicevic, S., Pietrangelo, A., Lin, H. Y., & Babitt, J. L. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.07.044 · Cited by 109 · see citing works
Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload
Barisani, D., Pelucchi, S., Mariani, R., Galimberti, S., Trombini, P., Fumagalli, D., Meneveri, R., Nemeth, E., Ganz, T., & Piperno, A. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.03.011 · Cited by 106 · see citing works
“HFE and TfR2 may interact and function as an iron sensor [33], whereas hemojuvelin acts as a BMP co-receptor and likely regulates hepcidin transcription through the BMP/SMAD pathway [25].”
BackgroundRegulation of iron pathways in response to hypoxia
Chepelev, N. L., & Willmore, W. G. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.12.023 · Cited by 102 · see citing works
“Interestingly, HFE was found to induce hepcidin expression when HFE was dissociated from TfR1 [136] such that HFE was proposed to act as a serum iron sensor [137].”
BackgroundCorradini, E., Rozier, M., Meynard, D., Odhiambo, A., Lin, H. Y.-F., Feng, Q., Migas, M. C., Britton, R. S., Babitt, J. L., & Fleming, R. E. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.077 · Cited by 102 · see citing works
Iron storage disease: Facts, fiction and progress
Beutler, E. (2007) · Blood Cells, Molecules, and Diseases · doi:10.1016/j.bcmd.2007.03.009 · Cited by 101 · see citing works
“The recent proposal [11] that a complex consisting of HFE, transferrin receptor 2, and hemojuvelin serves as a receptor for a bone morphogenetic protein (BMP) has attractive features, but does not explain our finding that the response to BMPs is undiminished in cells deficient either in HFE or transferrin receptor 2 […”
BackgroundHereditary hemochromatosis in the post- HFE era
Olynyk, J. K., Trinder, D., Ramm, G. A., Britton, R. S., & Bacon, B. R. (2008) · Hepatology · doi:10.1002/hep.22507 · Cited by 95 · see citing works
Iron metabolism: current facts and future decisions
Tandara, L., & Salamunić, I. (2012) · Biochemia Medica · doi:10.11613/bm.2012.034 · Cited by 96 · see citing works
Iron metabolism and drug resistance in cancer
Kazan, H. H., Urfali‐Mamatoglu, C., & Gündüz, U. (2017) · BioMetals · doi:10.1007/s10534-017-0037-7 · Cited by 95 · see citing works
“…hemochromatosis protein and drug resistance Hereditary hemochromatosis protein (HFE) is an atypical major histocompatibility class I molecule that acts as an iron sensor by interacting with TfR1 and TfR2 and regulates cellular iron uptake and whole body iron homeostasis (Goswami and Andrews 2006).”
Iron and the liver: Update 2008
Deugnier, Y., Brissot, P., & Loréal, O. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.01.014 · Cited by 95 · see citing works
Interacting signals in the control of hepcidin expression
Darshan, D., & Anderson, G. J. (2009) · BioMetals · doi:10.1007/s10534-008-9187-y · Cited by 94 · see citing works
“When TfR2 and HFE are overexpressed in the same cell, they are able to interact ( Goswami and Andrews 2006 ).”
BackgroundGardenghi, S., Grady, R. W., & Rivella, S. (2010) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2010.08.003 · Cited by 96 · see citing works
“When the concentration of holoTf in the serum increases, both holoTf and Hfe bind to Tfr2, which is a protein homologous to Tfr1, although the relative affinity of Tfr2 for holoTf and Hfe is reduced compared to that of Tfr1 (67-69).”
BackgroundInfluentialVolke, M., Gale, D. P., Maegdefrau, U., Schley, G., Klanke, B., Bosserhoff, A.-K., Maxwell, P. H., Eckardt, K.-U., & Warnecke, C. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007875 · Cited by 93 · see citing works
“expression by reducing TfR2 signalling [37,38].”
Ineffective Erythropoiesis: Anemia and Iron Overload
Gupta, R., Musallam, K. M., Taher, A. T., & Rivella, S. (2017) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2017.11.009 · Cited by 92 · see citing works
Hepcidin and iron disorders: new biology and clinical approaches
Arezes, J., & Nemeth, E. (2015) · International Journal of Laboratory Hematology · doi:10.1111/ijlh.12358 · Cited by 88 · see citing works
“iron transferrin, by associating with and stabilizing other hepcidin regulators—transferrin receptor 2 [11]”
BackgroundBone morphogenic proteins in iron homeostasis
Xiao, X., Alfaro-Magallanes, V. M., & Babitt, J. L. (2020) · Bone · doi:10.1016/j.bone.2020.115495 · Cited by 88 · see citing works
“The iron proteins HFE, TFR2, TMPRSS6 modulate BMP-SMAD signaling to regulate hepcidin In addition to mutations in HJV, mutations in HFE (encoding human homeostatic iron regulator protein) and TFR2 (encoding transferrin receptor 2) also cause hemochromatosis characterized by hepcidin deficiency and iron overload [56–59…”
BackgroundInfluentialTargeting the Hepcidin-Ferroportin Axis in the Diagnosis and Treatment of Anemias
Nemeth, E. (2009) · Advances in Hematology · doi:10.1155/2010/750643 · Cited by 87 · see citing works
“HFE, a protein similar to MHC I type molecules, appears to function as a shuttle between TfR1 and TfR2 depending on iron-transferrin concentrations [27].”
Sanad, M., Osman, M., & Gharib, A. (2011) · Italian Journal of Pediatrics · doi:10.1186/1824-7288-37-34 · Cited by 85 · see citing works
“All are found to interact with liver cells to initiate the production of sufficient hepcidin for correct maintenance of iron homeostasis [14-17].”
BackgroundRegulators of hepcidin expression
Roth, M., Meynard, D., & Coppin, H. (2019) · Vitamins and hormones · doi:10.1016/bs.vh.2019.01.005 · Cited by 84 · see citing works
Nemeth, E. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05585.x · Cited by 86 · see citing works
Chen, J., Chloupková, M., Gao, J., Arvedson, T., & Enns, C. A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706720200 · Cited by 81 · see citing works
Poli, M., Luscieti, S., Gandini, V., Maccarinelli, F., Finazzi, D., Silvestri, L., Roetto, A., & Arosio, P. (2010) · Haematologica · doi:10.3324/haematol.2010.027003 · Cited by 81 · see citing works
Pathophysiological consequences and benefits of HFE mutations: 20 years of research
Hollerer, I., Bachmann, A., & Muckenthaler, M. U. (2017) · Haematologica · doi:10.3324/haematol.2016.160432 · Cited by 80 · see citing works
A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis
Girelli, D., Trombini, P., Busti, F., Campostrini, N., Sandri, M. F., Pelucchi, S., Westerman, M., Ganz, T., Nemeth, E., Piperno, A., et al. (2010) · Haematologica · doi:10.3324/haematol.2010.033449 · Cited by 79 · see citing works
“The HFETFR2 complex is proposed to trigger hepcidin activation in response to increased holotransferrin concentration.(16,17) Loss of both HFE and TFR2 activity was reported to cause the phenotype of severe juvenile hemochromatosis in a single patient.”
BackgroundHepatocyte-targeted HFE and TFR2 control hepcidin expression in mice
Gao, J., Chen, J., Domenico, I. D., Koeller, D. M., Harding, C. O., Fleming, R. E., Koeberl, D. D., & Enns, C. A. (2010) · Blood · doi:10.1182/blood-2009-09-245209 · Cited by 79 · see citing works
Zumbrennen‐Bullough, K. B., & Babitt, J. L. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft443 · Cited by 80 · see citing works
Olynyk, J. K., & Ramm, G. A. (2022) · New England Journal of Medicine · doi:10.1056/nejmra2119758 · Cited by 78 · see citing works
Khalil, S., Holy, M., Grado, S., Fleming, R. E., Kurita, R., Nakamura, Y., & Goldfarb, A. N. (2017) · Blood Advances · doi:10.1182/bloodadvances.2016003772 · Cited by 78 · see citing works
- Authors
- Goswami, T., & Andrews, N. C.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Andrews, Nancy C.
- ORCID
- Andrews, Nancy C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 281
- Issue
- 39
- Pages
- 28494-28498
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1983970155
- Cited by
- 352
- References
- 20
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 1 · 2023: 6 · 2022: 4 · 2021: 15 · 2020: 13 · 2019: 12 · 2018: 12 · 2017: 18 · 2016: 16 · 2015: 16 · 2014: 18 · 2013: 31 · 2012: 17
- FWCI
- 19.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK53813, R01DK053813)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- hereditary hemochromatosis, HFE gene, transferrin receptor 2, transferrin receptor 1, protein-protein interaction, iron homeostasis, iron sensing, disease-associated mutations
- MeSH terms
- Hemochromatosis Protein, Animals, Hemochromatosis, Homeostasis, Humans, Iron, Membrane Proteins, Models, Biological, Mutation, Receptors, Transferrin, Histocompatibility Antigens Class I, Antigens, CD, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
