The DOI matches its Crossref record; 50 of the 52 references it cites were found in a registry or an index.
Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
Abstract
Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
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?
In the citing paper
“The latter is due to the fact, that several co-factors expressed on the hepatocyte cell membrane such as HFE, hemojuvelin (HJV) or TfR2 impact on hepcidin expression via the BMP-SMAD pathway (Babitt et al., 2006).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Babitt et al., 2006
In the citing paper
“Regulation of hepcidin by iron depends on the hemojuvelin (HJV) and bone morphogenetic protein receptor (BMPR) complex activating the SMAD signaling pathway (Fig 3) [13–15].”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [13]
In the citing paper
“HJV is a BMP co-receptor that enhances iron signaling to hepcidin (Babitt et al., 2006).”
From Pharmacological Targeting of the Hepcidin/Ferroportin Axis (2016) · cites this paper as Babitt et al., 2006
In the citing paper
“BMP6 binds to a heterodimeric receptor complexed with hemojuvelin (HJV) and matriptase-2 (the gene product of TMPRSS6), and stimulates HAMP expression [66, 67].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [67]
In the citing paper
“Nonetheless, BMP treatment is a potent stimulus for hepcidin expression both in cultured cells 113,114,116,117 and in animals.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [114]
In the citing paper
“They showed that hemojuvelin acts as a BMP coreceptor to stimulate hepcidin transcription.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [114]
In the citing paper
“Activation of signaling through the hemochromatosis protein HFE, TFR1, TFR2, or hemojuvelin (HJV), which acts as a co-receptor for bone morphogenetic protein 6 (BMP6), increases hepcidin transcription in a SMAD-dependent fashion.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [200]
In the citing paper
“HFE2 is a BMP coreceptor, and its mutation suppresses BMP signaling (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“An alternative mechanism of hepcidin regulation through a signaling pathway involving hemojuvelin (HFE2, also known as HJV) and bone morphogenetic proteins (BMP) was recently identified (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“This study showed that BMP could upregulate hepcidin in hepatocytes.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“hepatocytes deficient in HFE2 had impaired hepcidin induction by BMP signaling (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“Overexpression of HFE2 enhanced hepcidin production.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“Smad4-knockout mice had lower levels of hepcidin and did not induce hepcidin in response to iron loading or IL-6 stimulation (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“downstream activation of Smad4 was required for BMP-mediated hepcidin upregulation,”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
Citations
Cites
Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus
Shi, Y., & Massagué, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00432-x · Cited by 5,860
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
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., & Ganz, T. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420945 · Cited by 2,650
Hepcidin, a urinary antimicrobial peptide synthesized in the liver
Park, C. H., Valore, E. V., Waring, A. J., & Ganz, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008922200 · Cited by 2,168
Bone morphogenetic proteins: multifunctional regulators of vertebrate development.Preprint
Hogan, B. L. M. (1996) · Genes & Development · doi:10.1101/gad.10.13.1580 · Cited by 1,964
Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., & Gauthier, J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.11.3091 · Cited by 1,793
Hentze, M. W., Muckenthaler, M. U., & Andrews, N. C. (2004) · Cell · doi:10.1016/s0092-8674(04)00343-5 · Cited by 1,736
Self-citationPigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., & Loréal, O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008923200 · Cited by 1,697
Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein
Nemeth, E., Valore, E. V., Territo, M., Schiller, G., Lichtenstein, A., & Ganz, T. (2003) · Blood · doi:10.1182/blood-2002-10-3235 · Cited by 1,417
LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity
Krause, A., Neitz, S., Mägert, H.-J., Schulz, A., Forssmann, W.-G., Schulz-Knappe, P., & Adermann, K. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01920-7 · Cited by 1,324
Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A., & Vaulont, S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151179498 · Cited by 1,233
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
Defects in Adaptive Energy Metabolism with CNS-Linked Hyperactivity in PGC-1α Null Mice
Lin, J., Wu, P.-H., Tarr, P. T., Lindenberg, K. S., St-Pierre, J., Zhang, C.-Y., Mootha, V. K., Jäger, S., Vianna, C. R., Reznick, R. M., et al. (2004) · Cell · doi:10.1016/j.cell.2004.09.013 · Cited by 1,162
Mutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis
Papanikolaou, G., Samuels, M. E., Ludwig, E. H., MacDonald, M. L. E., Franchini, P. L., Dubé, M.-P., Andres, L., MacFarlane, J., Sakellaropoulos, N., Politou, M., et al. (2004) · Nature Genetics · doi:10.1038/ng1274 · Cited by 974
Korchynskyi, O., & ten Dijke, P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111023200 · Cited by 876
Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis
Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., Loukopoulos, D., & Camaschella, C. (2003) · Nature Genetics · doi:10.1038/ng1053 · Cited by 860
Alonso, S., Minty, A. J., Bourlet, Y., & BUCKINGHAM, M. E. (1986) · Journal of Molecular Evolution · doi:10.1007/bf02100994 · Cited by 643
Extracellular Regulation of BMP Signaling in Vertebrates: A Cocktail of Modulators
Balemans, W., & Hul, W. V. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0779 · Cited by 616
A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression
Wang, R.-H., Li, C., Xu, X., Zheng, Y., Xiao, C., Zerfas, P., Cooperman, S., Eckhaus, M., Rouault, T., Mishra, L., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.10.010 · Cited by 614
Regulation of hepcidin transcription by interleukin-1 and interleukin-6
Lee, P. L., Peng, H., Gelbart, T., Wang, L., & Beutler, E. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409808102 · Cited by 542
Structural basis of BMP signalling inhibition by the cystine knot protein Noggin
Groppe, J. C., Greenwald, J., Wiater, E., Rodríguez‐León, J., Economides, A. N., Kwiatkowski, W., Affolter, M., Vale, W., Belmonte, J. C. I., & Choe, S. (2002) · Nature · doi:10.1038/nature01245 · Cited by 534
Specific Activation of Smad1 Signaling Pathways by the BMP7 Type I Receptor, ALK2
Macías‐Silva, M., Hoodless, P. A., Tang, S. J., Buchwald, M., & Wrana, J. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.40.25628 · Cited by 476
Frolik, C. A., Wakefield, L. M., Smith, D. M., & Sporn, M. B. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)90612-5 · Cited by 471
Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload
Niederkofler, V. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25683 · Cited by 371
A mouse model of juvenile hemochromatosis
Huang, F. W. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25049 · Cited by 369
Consequences of knocking out BMP signaling in the mouse
Zhao, G.-Q. (2002) · genesis · doi:10.1002/gene.10167 · Cited by 361
What do BMPs do in mammals? Clues from the mouse short-ear mutation
Kingsley, D. M. (1994) · Trends in Genetics · doi:10.1016/0168-9525(94)90014-0 · Cited by 293
RGM is a repulsive guidance molecule for retinal axons
Monnier, P. P., Sierra, A., Macchi, P., Deitinghoff, L., Andersen, J., Mann, M., Flad, M., Hornberger, M. R., Stahl, B., Bonhoeffer, F., et al. (2002) · Nature · doi:10.1038/nature01041 · Cited by 293
Neogenin mediates the action of repulsive guidance molecule
Rajagopalan, S., Deitinghoff, L., Davis, D., Conrad, S., Skutella, T., Chédotal, A., Mueller, B. K., & Strittmatter, S. M. (2004) · Nature Cell Biology · doi:10.1038/ncb1156 · Cited by 276
RGM and its receptor neogenin regulate neuronal survival
Matsunaga, E., Tauszig-Delamasure, S., Monnier, P. P., Mueller, B. K., Strittmatter, S. M., Mehlen, P., & Chédotal, A. (2004) · Nature Cell Biology · doi:10.1038/ncb1157 · Cited by 267
Courselaud, B., Pigeon, C., Inoue, Y., Inoue, J., Gonzalez, F. J., Leroyer, P., Gilot, D., Boudjema, K., Guguen-Guillouzo, C., Brissot, P., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202653200 · Cited by 245
Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin
Lin, L., Goldberg, Y. P., & Ganz, T. (2005) · Blood · doi:10.1182/blood-2005-05-1845 · Cited by 241
DRAGON, a Bone Morphogenetic Protein Co-receptor
Samad, T. A., Rebbapragada, A., Bell, E. J. D. H., Zhang, Y. E., Sidis, Y., Jeong, S., Campagna, J. A., Perusini, S. J., Fabrizio, D. A., Schneyer, A. L., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m410034200 · Cited by 228
Repulsive Guidance Molecule (RGMa), a DRAGON Homologue, Is a Bone Morphogenetic Protein Co-receptor
Babitt, J. L., Zhang, Y. E., Samad, T. A., Xia, Y. Y., Tang, J., Campagna, J. A., Schneyer, A. L., Woolf, C. J., & Lin, H. Y.-F. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503511200 · Cited by 202
Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis
Lanzara, C. (2004) · Blood · doi:10.1182/blood-2004-01-0192 · Cited by 184
Niederkofler, V., Salie, R., Sigrist, M., & Arber, S. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4610-03.2004 · Cited by 179
Clarke, T. R., Hoshiya, Y., Yi, S. E., Liu, X., Lyons, K. M., & Donahoe, P. K. (2001) · Molecular Endocrinology · doi:10.1210/mend.15.6.0664 · Cited by 177
Recent advances in the isolation of liver cells
Alpini, G. D., Phillips, J. O., Vroman, B. T., & LaRusso, N. F. (1994) · Hepatology · doi:10.1002/hep.1840200231 · Cited by 176
Transforming growth factor-β gene expression in normal and fibrotic rat liver
Bleser, P. J. D., Niki, T., Rogiers, V., & Geerts, A. E. (1997) · Journal of Hepatology · doi:10.1016/s0168-8278(97)80257-7 · Cited by 169
Miller, A. F., Harvey, S. A. K., Thies, R. S., & Olson, M. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.24.17937 · Cited by 166
Zhang, A., West, A. P., Wyman, A. E., Björkman, P. J., & Enns, C. A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506207200 · Cited by 149
Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin
Lee, P. L., Beutler, E., Rao, S. V., & Barton, J. C. (2004) · Blood · doi:10.1182/blood-2004-01-0072 · Cited by 139
Samad, T. A., Srinivasan, A., Karchewski, L. A., Jeong, S., Campagna, J. A., Ji, R., Fabrizio, D. A., Zhang, Y., Lin, H. Y.-F., Bell, E. J. D. H., et al. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4115-03.2004 · Cited by 106
Piscione, T. D., Phan, T., & Rosenblum, N. D. (2001) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.2001.280.1.f19 · Cited by 97
Krijt, J., Vokurka, M., Chang, K., & Nečas, E. (2004) · Blood · doi:10.1182/blood-2004-06-2422 · Cited by 69
Kanzler, S., Meyer, E., Lohse, A. W., Schirmacher, P., Henninger, J., Galle, P. R., & Blessing, M. (2001) · Oncogene · doi:10.1038/sj.onc.1204544 · Cited by 66
Identification of a novel mutation (C321X) in HJV
Huang, F. W., Rubio‐Aliaga, I., Kushner, J. P., Andrews, N. C., & Fleming, M. D. (2004) · Blood · doi:10.1182/blood-2004-01-0400 · Cited by 63
Knittel, T. E., Fellmer, P., Müller, L. P., & Ramadori, G. P. (1997) · Experimental Cell Research · doi:10.1006/excr.1997.3504 · Cited by 58
del Re, E. C., Babitt, J. L., Pirani, A., Schneyer, A. L., & Lin, H. Y.-F. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401350200 · Cited by 54
Hepatic and extrahepatic expression of the new iron regulatory protein hemojuvelin.
Rodriguez-Martinez, A., Niemelä, O. J., & Parkkila, S. (2004) · PubMed · Cited by 48
Cited by
Sorted by citations
Weiss, G., & Goodnough, L. T. (2005) · New England Journal of Medicine · doi:10.1056/nejmra041809 · Cited by 3,800
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
Highly Recurrent TERT Promoter Mutations in Human Melanoma
Huang, F. W., Hodis, E., Xu, M. J., Kryukov, G. V., Chin, L., & Garraway, L. A. (2013) · Science · doi:10.1126/science.1229259 · Cited by 1,816
“25μg of pRL-TK (Promega), a control Renilla luciferase vector (12, 13).”
A Red carpet for iron metabolism
Muckenthaler, M. U., Rivella, S., Hentze, M. W., & Galy, B. (2017) · Cell · doi:10.1016/j.cell.2016.12.034 · Cited by 1,319
Ganz, T., & Nemeth, E. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.01.014 · Cited by 1,282
Metadata
- Authors
- Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., Andrews, N. C., & Lin, H. Y.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lin, Herbert Y
- ORCID
- Venue
- Nature Genetics
- Published
- 2006-04-09
- Volume
- 38
- Issue
- 5
- Pages
- 531-539
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2050833520
- Cited by
- 1,026
- References
- 52
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 21 · 2023: 22 · 2022: 21 · 2021: 54 · 2020: 35 · 2019: 39 · 2018: 39 · 2017: 50 · 2016: 44 · 2015: 50 · 2014: 58 · 2013: 62 · 2012: 67
- FWCI
- 49.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL07623, T32HL007623)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-71837, R01DK066373, DK-69533, K08DK075846, R01DK071837, F32DK068997, R01DK069533)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- hemojuvelin, hepcidin, BMP signaling, iron homeostasis, hemochromatosis, RGMa, dragons, hepatocytes, iron overload, anemia
- MeSH terms
- Hemochromatosis Protein, Amino Acid Sequence, Animals, Gene Expression Regulation, Cricetinae, Humans, Liver, Membrane Proteins, Molecular Sequence Data, Mutation, Signal Transduction, Polymerase Chain Reaction, Transforming Growth Factor beta, CHO Cells, Bone Morphogenetic Proteins, Antimicrobial Cationic Peptides, Bone Morphogenetic Protein 2, GPI-Linked Proteins, Hepcidins
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
