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
Flagged first, then by citations
2 of the 52 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 501–600 of 999
Nerve growth factor promotes osteogenic differentiation of MC3T3-E1 cells via BMP-2/Smads pathway
Yang, X., Mou, D., Yu, Q., Zhang, J., Xiong, Y., Zhang, Z., & Xing, S. (2021) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2021.151819 · Cited by 34
Dragon Enhances BMP Signaling and Increases Transepithelial Resistance in Kidney Epithelial Cells
Xia, Y. Y., Babitt, J. L., Bouley, R., Zhang, Y., Silva, N. D., Chen, S., Zhuang, Z., Samad, T. A., Brenner, G. J., Anderson, J. L., et al. (2010) · Journal of the American Society of Nephrology · doi:10.1681/asn.2009050511 · Cited by 34
Influence of post-exercise hypoxic exposure on hepcidin response in athletes
Badenhorst, C. E., DAWSON, B. T., Goodman, C., Sim, M., Cox, G. R., Gore, C. J., Tjalsma, H., Swinkels, D. W., & Peeling, P. (2014) · European Journal of Applied Physiology · doi:10.1007/s00421-014-2829-6 · Cited by 35
Implications of altered iron homeostasis for age-related macular degeneration
Błasiak, J. (2010) · Frontiers in bioscience · doi:10.2741/3804 · Cited by 35
Dragon (repulsive guidance molecule b, RGMb) is a novel gene that promotes colorectal cancer growth
Shi, Y., Chen, G.-B., Huang, X., Xiao, C., Wang, H., Li, Y., Zhang, J., Li, S., Xia, Y. Y., Ren, J., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4110 · Cited by 33
“RGMc, also named hemojuvelin (HFE2/HJV), positively regulates hepcidin, a key regulator of systemic iron homeostasis [21].”
BackgroundRegulation of Iron Absorption in Hemoglobinopathies
Rechavi, G., & Rivella, S. (2008) · Current Molecular Medicine · doi:10.2174/156652408786241401 · Cited by 32
Hepcidin Levels Are Increased in Patients with Acute Ischemic Stroke: Preliminary Report
Słomka, A., Świtońska, M., & Żekanowska, E. (2015) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2015.03.031 · Cited by 32
Gkouvatsos, K., Fillebeen, C., Daba, A., Wagner, J., Sebastiani, G., & Pantopoulos, K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085530 · Cited by 33
“Considering that Hjv operates biochemically as BMP co-receptor [14] our data suggest that Hjv is essential for enhancing and amplifying iron-dependent BMP6/Smad signaling to liver hepcidin.”
BackgroundInvestigational therapies for renal disease-induced anemia
Schmid, H., & JELKMANN, W. E. B. (2016) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2016.1182981 · Cited by 33
Antiviral activity of bone morphogenetic proteins and activins
Eddowes, L. A., Al-Hourani, K., Ramamurthy, N., Frankish, J., Baddock, H. T., Sandor, C., Ryan, J. D., Fusco, D. N., Arezes, J., Giannoulatou, E., et al. (2018) · Nature Microbiology · doi:10.1038/s41564-018-0301-9 · Cited by 32
Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6-/- mice
Pauk, M., Grgurević, L., Brkljačić, J. M., Kufner, V., Bordukalo-Nikšić, T., Grabušić, K., Razdorov, G., Rogić, D., Žuvić, M., Oppermann, H., et al. (2014) · International Orthopaedics · doi:10.1007/s00264-014-2550-4 · Cited by 33
“Previous studies demonstrated that BMP2, 4 and 5 can all bind to hemojuvelin, the BMP coreceptor that plays an essential role in hepcidin regulation and iron homeostasis [9], with high affinity (KD’s 4.”
BackgroundInfluentialTruksa, J., Lee, P. L., & Beutler, E. (2007) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2007.06.014 · Cited by 33
BMPER Protein Is a Negative Regulator of Hepcidin and Is Up-regulated in Hypotransferrinemic Mice
Patel, N., Masaratana, P., Díaz‐Castro, J., Latunde-Dada, G. O., Qureshi, A., Lockyer, P. P., Jacob, M., Arno, M. J., Matak, P., Mitry, R. R., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.310789 · Cited by 33
Rare Types of Genetic Hemochromatosis
Camaschella, C., & Poggiali, E. (2009) · Acta Haematologica · doi:10.1159/000243798 · Cited by 35
“It is likely that different genetic modifiers are present in cases of different racial background. Pathophysiology At the time of its discovery, the role of HJV in iron metabolism was ambiguous, although the extremely low levels of hepcidin found in patients with HJV mutations suggested a function upstream of hepcidin…”
BackgroundGenes determining blood cell traits
Andrews, N. C. (2009) · Nature Genetics · doi:10.1038/ng1109-1161 · Cited by 33
Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice
Díaz, V., Gammella, E., Recalcati, S., Santambrogio, P., Naldi, A. M., Vogel, J., Gassmann, M., & Cairo, G. (2013) · Hepatology · doi:10.1002/hep.26550 · Cited by 33
New and old players in the hepcidin pathway
Camaschella, C., & Silvestri, L. (2008) · Haematologica · doi:10.3324/haematol.13724 · Cited by 33
Understanding the Intricacies of Iron Overload Associated with β-Thalassemia: A Comprehensive Review
Basu, S., Rahaman, M., Dolai, T. K., Shukla, P. C., & Chakravorty, N. (2023) · Thalassemia Reports · doi:10.3390/thalassrep13030017 · Cited by 37
“A membrane protein, Hemojuvelin (Hjv), is reported to vitally regulate the expression of the HAMP gene in the liver, which acts via the Bone Morphogenetic Protein (BMP) signaling pathway [63].”
BackgroundHfe and Hjv exhibit overlapping functions for iron signaling to hepcidin
KENT, P. G., Wilkinson, N., Constante, M., Fillebeen, C., Gkouvatsos, K., Wagner, J., Buffler, M., Becker, C., Schümann, K., Santos, M. M., et al. (2015) · Journal of Molecular Medicine · doi:10.1007/s00109-015-1253-7 · Cited by 32
Iron and oxygen sensing: a tale of 2 interacting elements?
Simpson, R. J., & McKie, A. T. (2014) · Metallomics · doi:10.1039/c4mt00225c · Cited by 32
Lv, T., Zhang, W., Xu, A., Li, Y., Zhou, D., Zhang, B., Li, X., Zhao, X., Wang, Y., Wang, X., et al. (2018) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2018-105348 · Cited by 32
Simão, M., & Cancela, M. L. (2021) · Biochemical Society Transactions · doi:10.1042/bst20200672 · Cited by 32
Low Serum Hepcidin in Patients with Autoimmune Liver Diseases
Lyberopoulou, A., Chachami, G., Gatselis, N., Kyratzopoulou, E., Saitis, A., Gabeta, S., Eliades, P., Paraskeva, E., Zachou, K., Koukoulis, G. Κ., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0135486 · Cited by 35
“Up-regulation of hepcidin under iron-replete hepatic conditions involves the BMP/ SMAD-signaling pathway [6, 12, 13] while its up-regulation by elevated transferin-bound iron additionally involves HFE, transferin receptor 2 (Tfr2) and HJV [14–16].”
BackgroundA critical role for murine transferrin receptor 2 in erythropoiesis during iron restriction
Wallace, D. F., Secondes, E. S., Rishi, G., Ostini, L., McDonald, C. J., Lane, S., Vu, T., Hooper, J. D., Velasco, G., Ramsay, A. J., et al. (2014) · British Journal of Haematology · doi:10.1111/bjh.13225 · Cited by 31
Guillem, F., Kannengiesser, C., Oudin, C., Lenoir, A., Matak, P., Donadieu, J., Isidor, B., Mechinaud, F. M., Aguilar‐Martinez, P., Beaumont, C., et al. (2012) · Human Mutation · doi:10.1002/humu.22116 · Cited by 31
“HJV, a GPI-linked membrane protein synthesized by the hepatocytes, is a BMP6 coreceptor [Babitt et al., 2006; Xia et al., 2008].”
BackgroundRegulators and effectors of bone morphogenetic protein signalling in the cardiovascular system
Luo, J., Zhang, Y., Wang, L., & Huang, Y. (2015) · The Journal of Physiology · doi:10.1113/jp270207 · Cited by 31
“RGMs including RGMa, RGMb (Dragon) and RGMc (hemojuvelin) are co-receptors for BMP2 and BMP4 to enhance their signal transduction (Babitt et al. 2005, 2006; Samad et al. 2005), while RGMa can also facilitate BMP2 and BMP4 to utilize ActR-II as their type II receptor (Xia et al. 2007).”
BackgroundKoliaraki, V., Marinou, M., Samiotaki, M. K., Panayotou, G., Pantopoulos, K., & Mamalaki, A. (2008) · Biochimie · doi:10.1016/j.biochi.2008.01.012 · Cited by 30
Liver hemojuvelin protein levels in mice deficient in matriptase-2 (Tmprss6)
Krijt, J., Fujikura, Y., Ramsay, A. J., Velasco, G., & Nečas, E. (2011) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2011.04.009 · Cited by 31
“Hjv interacts with bone morphogenetic protein ligands [4], and this interaction at the hepatocyte membrane initiates a cascade of intracellular phosphorylations which ultimately lead to an increase in hepcidin gene transcription.”
BackgroundAntosiewicz, J., Kaczor, J. J., Kasprowicz, K., Laskowski, R., Kujach, S., Łuszczyk, M., Radzimiński, Ł., & Ziemann, E. (2013) · Cellular Immunology · doi:10.1016/j.cellimm.2013.06.006 · Cited by 31
Maegdefrau, U., Arndt, S., Kivorski, G., Hellerbrand, C., & Bosserhoff, A. (2011) · Laboratory Investigation · doi:10.1038/labinvest.2011.123 · Cited by 31
“Flag-tagged human HJV expression plasmid was a generous gift from Herbert Y Lin (Harvard Medical School, Boston, MA, USA).(3) HNF-1a and antisense snail (as-snail) expression constructs were previously described.”
BackgroundMethodParajes, S., González‐Quintela, A., Franco, J. C., Quinteiro, C., Domínguez, F., & Loidi, L. (2010) · BMC Genetics · doi:10.1186/1471-2156-11-110 · Cited by 32
“This data together with the fact that HAMP is regulated by many different signals [6,10,15-18,20-22] suggested that the effect of the c.”
Hemojuvelin N-terminal mutants reach the plasma membrane but do not activate the hepcidin response
Pagani, A., Silvestri, L., Nai, A., & Camaschella, C. (2008) · Haematologica · doi:10.3324/haematol.12508 · Cited by 31
“Membrane-HJV (m-HJV) is a co-receptor for bone morphogenetic protein (BMP), which participates in the activation of hepcidin transcription.(8,9) HJV also exists as a soluble protein (s-HJV) produced by furin cleavage and secreted into the extracellular environment.”
BackgroundLu, H., Lian, L., Shi, D., Zhao, H., & Dai, Y. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.2769 · Cited by 30
“iron-sensing and signaling pathway, which regulates hepcidin synthesis (31,32).”
Clinical, laboratory, and hemostatic findings in cats with naturally occurring sepsis
Klainbart, S., Agi, L., Bdolah‐Abram, T., Kelmer, E., & Aroch, I. (2017) · Journal of the American Veterinary Medical Association · doi:10.2460/javma.251.9.1025 · Cited by 30
Iron overload in patients with myelodysplastic syndromes: An updated overview
Moukalled, N. M., Rassi, F. A. E., Temraz, S. N., & Taher, A. T. (2018) · Cancer · doi:10.1002/cncr.31550 · Cited by 31
“kinase/signal transducer and activator of transcription (JAK-STAT3) activated by the inflammatory cytokine interleukin 6, in addition to the bone morphogenetic protein receptor (BMPR-SMAD) signaling pathways.(9) The interaction between the BMP molecule and its co-receptor, the hemojuvelin protein, activates this pathw…”
BackgroundIroning Out the Pathogenesis of Acute Kidney Injury
Hingorani, S., Molitoris, B. A., & Himmelfarb, J. (2009) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2009.01.002 · Cited by 30
Blunted hepcidin response to inflammation in the absence of Hfe and transferrin receptor 2
Wallace, D. F., McDonald, C. J., Ostini, L., & Subramaniam, V. N. (2011) · Blood · doi:10.1182/blood-2010-08-303859 · Cited by 29
Iron metabolism: microbes, mouse, and man
Latunde‐Dada, G. O. (2009) · BioEssays · doi:10.1002/bies.200900101 · Cited by 29
“It exerts this function through the BMP/SMAD4 signaling pathway.((82,84)) BMP6, which is regulated by iron, is crucial in this process.”
BackgroundEndofin, a novel BMP-SMAD regulator of the iron-regulatory hormone, hepcidin
Goh, J. B., Wallace, D. F., Hong, W., & Subramaniam, V. N. (2015) · Scientific Reports · doi:10.1038/srep13986 · Cited by 29
Molecular Mechanisms Regulating Hepcidin Revealed by Hepcidin Disorders
Camaschella, C., & Silvestri, L. (2011) · The Scientific World JOURNAL · doi:10.1100/tsw.2011.130 · Cited by 28
“TMPRSS6 transcription is increased in vitro in hypoxia[59] and might inhibit hepcidin, decreasing the BMP coreceptor HJV on the cell surface[43].”
BackgroundInfluentialInflammation Regulates TMPRSS6 Expression via STAT5
Meynard, D., Sun, C. C., Wu, Q., Chen, W., Chen, S., Nelson, C. N., Waters, M. J., Babitt, J. L., & Lin, H. Y.-F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0082127 · Cited by 36
“To further explore a causative role for the BMP-SMAD pathway, we injected LPS into Hjv mice, where the Bmp-Smad pathway is inhibited [18].”
MethodMechanisms and Regulation of Intestinal Iron Transport
Collins, J. F., Flores, S. R., Wang, X., & Anderson, G. J. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809954-4.00060-8 · Cited by 30
Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6
Lee, P. L., Hsu, M., Welser-Alves, J. V., & Peng, H. (2012) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2011.12.005 · Cited by 31
Korenaga, M., Nishina, S., Korenaga, K., Tomiyama, Y., Yoshioka, N., Hara, Y., Sasaki, Y., Shimonaka, Y., & Hino, K. (2014) · Liver International · doi:10.1111/liv.12675 · Cited by 29
“Another pathway that regulates hepcidin expression involves the TGF-b/ bone morphogenetic protein superfamily (27, 28).”
BackgroundThe neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans
Tian, C., Shi, H., Xiong, S., Hu, F., Xiong, W., & Liu, J. (2013) · Development · doi:10.1242/dev.099838 · Cited by 29
Hepcidin: a real-time biomarker of iron need
Hare, D. J. (2017) · Metallomics · doi:10.1039/c7mt00047b · Cited by 29
Iron-mediated retinal degeneration in haemojuvelin-knockout mice
Gnana‐Prakasam, J. P., Tawfik, A. M., Romej, M., Ananth, S., Martin, P. M., Smith, S. B., & Ganapathy, V. (2011) · Biochemical Journal · doi:10.1042/bj20111148 · Cited by 29
Review article: the genetic basis of haemochromatosis
Griffiths, W. J. H. (2007) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2007.03387.x · Cited by 31
Immunoassay for human serum hemojuvelin
Brasse‐Lagnel, C., Poli, M., Lesueur, C., Grandchamp, B., Lavoinne, A., Beaumont, C., & Bekri, S. (2010) · Haematologica · doi:10.3324/haematol.2010.022129 · Cited by 28
“Cell-associated hemojuvelin acts as a co-receptor of bone morphogenic proteins to enhance hepcidin expression through the Smad pathway.(2,3) In contrast, soluble hemojuvelin, by binding bone morphogenic proteins, acts as a competitive antagonist of membrane-bound hemojuvelin, leading to decreased hepcidin expression.”
BackgroundRepulsive guidance molecules lock growth differentiation factor 5 in an inhibitory complex
Malinauskas, T., Peer, T. V., Bishop, B., Mueller, T. D., & Siebold, C. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2000561117 · Cited by 28
Perez, E., Baker, J. R., Giandomenico, S. D., Kermani, P., Parker, J., Kim, K., Yang, J., Barnes, P. J., Vaulont, S., Scandura, J. M., et al. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901284 · Cited by 29
“signaling (15), and by a number of proinflammatory cytokines,”
Background20 years of Hepcidin: How far we have come
Colucci, S., Marques, O., & Altamura, S. (2021) · Seminars in Hematology · doi:10.1053/j.seminhematol.2021.05.001 · Cited by 28
Parrow, N. L., Gardenghi, S., Ramos, P., Casu, C., Grady, R. W., Anderson, E. R., Shah, Y. M., Li, H., Ginzburg, Y. Z., Fleming, R. E., et al. (2012) · Blood · doi:10.1182/blood-2012-01-405563 · Cited by 28
van den Heuvel, D. M. A., Hellemons, A. J. C. G. M., & Pasterkamp, R. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055828 · Cited by 27
The Role of Iron in Benign and Malignant Hematopoiesis
Sinha, S., Pereira-Reis, J., Guerra, A., Rivella, S., & Duarte, D. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8155 · Cited by 29
“HJV is a coreceptor of BMPs (9, 10, 173).”
Molecular Evolution of Hemojuvelin and the Repulsive Guidance Molecule Family
Camus, L. M., & Lambert, L. A. (2007) · Journal of Molecular Evolution · doi:10.1007/s00239-006-0241-5 · Cited by 27
“The ability of HJV to regulate hepcidin expression is apparently dependent on its binding with BMP as part of that signaling pathway ( Babitt et al. 2006 ).”
BackgroundInfluentialProtein Antioxidants in Thalassemia
Awadallah, S. M. (2013) · Advances in clinical chemistry · doi:10.1016/b978-0-12-407681-5.00003-9 · Cited by 27
Deferasirox Reduces Iron Overload in a Murine Model of Juvenile Hemochromatosis
Nick, H., ALLEGRINI, P. R., Fozard, L., Junker, U., Rojkjaer, L. P., Salie, R., Niederkofler, V., & O'Reilly, T. (2009) · Experimental Biology and Medicine · doi:10.3181/0811-rm-337 · Cited by 27
“pathway that leads from HJV to the expression of hepcidin has been made by the identification of bone morphogenetic protein (BMP) as a co-receptor of HJV, and that a HJV mutant associated with JH has impaired BMP signaling activity (7).”
BackgroundFoka, P., Dimitriadis, A., Kyratzopoulou, E., Giannimaras, D. A., Sarno, S., Simos, G., Georgopoulou, U., & Mamalaki, A. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1621-4 · Cited by 27
Hemojuvelin–hepcidin axis modeled and analyzed using Petri nets
Formanowicz, D., Kozak, A., Głowacki, T., Radom, M., & Formanowicz, P. (2013) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2013.07.013 · Cited by 28
Liver-gut axis in the regulation of iron homeostasis
Darshan, D. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i35.4737 · Cited by 31
“Cells transfected with the co-receptor HJV or treated with the ligand BMP-2 showed increased levels of hepcidin, and BMP-2 induction was enhanced in the presence of HJV[ 76 ].”
BackgroundInfluentialNew strategies to target iron metabolism for the treatment of beta thalassemia
Oikonomidou, P. R., Casu, C., & Rivella, S. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13018 · Cited by 27
Leitch, H. A., Buckstein, R. J., Zhu, N. Y., Nevill, T. J., Yee, K. W. L., Leber, B. F., Keating, M., St‐Hilaire, È., Kumar, R., Delage, R., et al. (2018) · Leukemia Research · doi:10.1016/j.leukres.2018.09.005 · Cited by 27
Effect of the new HJV-L165X mutation on penetrance of HFE
van Dijk, B. A. C., Kemna, E., Tjalsma, H., Klaver, S. M., Wiegerinck, E. T. G., Jp, G., Slee, P. H. T. J., Breuning, M. H., & Swinkels, D. W. (2007) · Blood · doi:10.1182/blood-2006-11-058560 · Cited by 27
Paköz, Z. B., Çekiç, C., Arabul, M., Sarıtaş Yüksel, E., İpek, S., Vatansever, S., & Ünsal, B. (2015) · Gastroenterology Research and Practice · doi:10.1155/2015/810942 · Cited by 26
Targeting and activation of macrophages in leishmaniasis. A focus on iron oxide nanoparticles
Palomino-Cano, C., Moreno, E., Irache, J. M., & Espuelas, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1437430 · Cited by 29
Regulation of hepcidin through GDF-15 in cancer-related anemia
Jiang, F., Yu, W., Wang, X.-H., Tang, Y., Guo, L., & Jiao, X. (2013) · Clinica Chimica Acta · doi:10.1016/j.cca.2013.10.015 · Cited by 28
The role of ClpX in erythropoietic protoporphyria
Whitman, J. C., Paw, B. H., & Chung, J. (2018) · Hematology Transfusion and Cell Therapy · doi:10.1016/j.htct.2018.03.001 · Cited by 26
BMP5 contributes to hepcidin regulation and systemic iron homeostasis in mice
Xiao, X., Xu, Y., Moschetta, G. A., Yu, Y., Fisher, A. L., Alfaro-Magallanes, V. M., McMillen, S. A., Phillips, S., Wang, C., Christian, J. L., et al. (2023) · Blood · doi:10.1182/blood.2022019195 · Cited by 25
Heritage, M. L., Murphy, T. L., Bridle, K. R., Anderson, G. J., Crawford, D. H., & Fletcher, L. M. (2009) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2009.00969.x · Cited by 27
BMP Signaling Modulates Hepcidin Expression in Zebrafish Embryos Independent of Hemojuvelin
Gibert, Y., Lattanzi, V. J., Zhen, A. W., Vedder, L. M., Brunet, F., Faasse, S. A., Babitt, J. L., Lin, H. Y.-F., Hammerschmidt, M., & Fraenkel, P. G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0014553 · Cited by 29
“Induction of bmp2b at 48 hpf stimulates hepcidin expression in zebrafish embryos BMP signaling has been shown to modulate hepcidin expression in adult mammals[9,20] and in adult zebrafish.”
InfluentialBéliveau, F., Brulé, C., Désilets, A., Zimmerman, B., Laporte, S. A., Lavoie, C. L., & Leduc, R. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.223461 · Cited by 26
Liu, W., Li, X., Zhao, Y., Meng, X., Wan, C., Yang, B., Lan, H.-Y., Lin, H. Y.-F., & Xia, Y. Y. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.517573 · Cited by 26
Sebastiani, G., Gkouvatsos, K., Maffettone, C., Busatto, G., Guido, M., & Pantopoulos, K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025138 · Cited by 26
“4A), in line with the function of Hjv as a BMP co-receptor that is necessary for iron-dependent signaling to hepcidin [11].”
BackgroundHattori, A., Tomosugi, N., Tatsumi, Y., Suzuki, A., Hayashi, K., Katano, Y., Inagaki, Y., Ishikawa, T., Hayashi, H., Goto, H., et al. (2012) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2012.01.002 · Cited by 25
Casanovas, G., Banerji, A., D’Alessio, F., Muckenthaler, M. U., & Legewie, S. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003421 · Cited by 26
“Information about iron blood levels is transduced from the hepatocyte cell membrane to the nucleus by the bone morphogenetic protein (BMP) signalling pathway [11,12]: Increasing iron blood concentrations are sensed by Hfe and Tfr2, two transmembrane proteins mutated in HH [13,14].”
BackgroundJiang, W. G. (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.1251 · Cited by 26
“also crucial as a co-receptor for Hepcidin expression induced by BMP-2 and BMP-4, thus to maintain systemic iron homeostasis (8).”
BackgroundExtrahepatic hepcidin production: The intriguing outcomes of recent years
Daher, R., Lefèbvre, T., Puy, H., & Karim, Z. (2019) · World Journal of Clinical Cases · doi:10.12998/wjcc.v7.i15.1926 · Cited by 26
Poli, M., Anower-E-Khuda, F., Asperti, M., Ruzzenenti, P., Gryzik, M., Denardo, A., Gordts, P. L. S. M., Arosio, P., & Esko, J. D. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.007213 · Cited by 25
“Various accessory proteins, some of which are specific to hepatocytes (5), include hemojuvelin (HJV), a Glycosylphosphatidylinositol (GPI)-anchor protein that acts as a BMP co-receptor (11), and the serine protease TMPRSS6 that controls HJV activity (12).”
BackgroundLévesque, J.-P., SUMMERS, K. M., Bisht, K., Millard, S. M., Winkler, I. G., & Pettit, A. R. (2021) · Experimental Hematology · doi:10.1016/j.exphem.2021.08.011 · Cited by 26
Zakrzewski, P. K. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10173900 · Cited by 27
DRAGON, a GPI‐anchored membrane protein, inhibits BMP signaling in C2C12 myoblasts
Kanomata, K., Kokabu, S., Nojima, J., Fukuda, T., & Katagiri, T. (2009) · Genes to Cells · doi:10.1111/j.1365-2443.2009.01302.x · Cited by 25
“These proteins bind to BMP ligands as well as type I and type II BMP receptors, thereby enhancing BMP signaling (Babitt et al. 2005, 2006; Samad et al. 2005).”
BackgroundMethodInfluentialFerroportin and Erythroid Cells: An Update
Cianetti, L., Gabbianelli, M., & Sposi, N. M. (2010) · Advances in Hematology · doi:10.1155/2010/404173 · Cited by 28
Robach, P., Recalcati, S., Girelli, D., Campostrini, N., Kempf, T., Wollert, K. C., Corbella, M., Santambrogio, P., Perbellini, L., Brasse‐Lagnel, C., et al. (2013) · European Journal Of Haematology · doi:10.1111/ejh.12122 · Cited by 25
“Another emerging factor is hemojuvelin (HJV), a repulsive guidance molecule mainly expressed in skeletal muscle and liver, which, in its cell-associated form, acts as a membrane co-receptor of bone morphogenetic proteins (BMP) to activate SMAD protein phosphorylation and ultimately hepcidin expression (11).”
BackgroundWang, C., Fang, Z., Zhu, Z., Liu, J., & Chen, H. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.05.002 · Cited by 25
Therapeutic Opportunities for Hepcidin in Acute Care Medicine
Chawla, L. S., Beers-Mulroy, B., & Tidmarsh, G. F. (2019) · Critical Care Clinics · doi:10.1016/j.ccc.2018.11.014 · Cited by 28
Mechanism and regulation of iron absorption throughout the life cycle
Qiu, L., Frazer, D. M., Hu, M., Song, R., Liu, X., Qin, X., Ma, J., Zhou, J., Tan, Z., Ren, F., et al. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.01.002 · Cited by 33
Li, P., Li, J., Yang, R., Zhang, F., Wang, H., Chu, H., Lu, Y., Dun, S., Wang, Y., Zang, W., et al. (2015) · Diagnostic Pathology · doi:10.1186/s13000-015-0297-x · Cited by 24
“RGM proteins can function as bone morphogenetic protein (BMP) coreceptors [32–34], which are members of the transforming growth factor beta (TGF-β) family of ligands and play a role in many biological activities.”
BackgroundIdentification of TMPRSS 6 cleavage sites of hemojuvelin
Rausa, M., Ghitti, M., Pagani, A., Nai, A., Campanella, A., Musco, G., Camaschella, C., & Silvestri, L. (2015) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12462 · Cited by 24
“To investigate the cleavage products of the N-terminal portion of HJV, in the absence of specific antibodies we took advantage of the HJV tag construct that in previous functional studies behaves as the wild-type protein [2].”
BackgroundMethodInfluentialProhepcidin binds to the HAMP promoter and autoregulates its own expression
Pandur, E., Sipos, K., Grama, L., Nagy, J., Poór, V. S., Sétáló, G., Miseta, A., & Fekete, Z. (2013) · Biochemical Journal · doi:10.1042/bj20121466 · Cited by 24
The nexus of iron and inflammation in hepcidin regulation: SMADs, STATs, and ECSIT
Milward, E. A., Johnstone, D. M., Trinder, D., Ramm, G. A., & Olynyk, J. K. (2006) · Hepatology · doi:10.1002/hep.21526 · Cited by 24
Bayele, H. K., & Srai, S. K. (2009) · Haematologica · doi:10.3324/haematol.2009.010793 · Cited by 24
Wang, K., Wu, J., Cheng, F., Huang, X. B., Zeng, F., & Zhang, Y. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/7601592 · Cited by 23
“BMPs bind to the BMP type II receptor and the BMP coreceptor hemojuvelin (HJV), which interact with the HFE/transferrin receptor-2 (TfR2) [22].”
BackgroundBrain iron metabolism and its perturbation in neurological diseases
Crichton, R. R., Dexter, D. T., & Ward, R. J. (2011) · Monatshefte für Chemie - Chemical Monthly · doi:10.1007/s00706-011-0472-z · Cited by 23
Schmidt, P. J., Andrews, N. C., & Fleming, M. D. (2010) · Blood · doi:10.1182/blood-2010-04-277954 · Cited by 23
Hepcidin expression in liver cells: evaluation of mRNA levels and transcriptional regulation
Kanamori, Y., Murakami, M., Matsui, T., & Funaba, M. (2014) · Gene · doi:10.1016/j.gene.2014.05.040 · Cited by 23
“The results indicate that BMP-induced hepcidin expression is partially a direct event, and that it is also enhanced through de novo protein synthesis; the results clearly disagree with a previous study using HepG2 cells in which cycloheximide did not affect BMP-induced hepcidin expression (Babitt et al., 2006).”
ResultClinical Perspectives on Hereditary Hemochromatosis
Ayonrinde, O. T., Milward, E. A., Chua, A. C. G., Trinder, D., & Olynyk, J. K. (2008) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360802335716 · Cited by 23
Molecular Mechanisms of Intestinal Iron Transport
Collins, J. F., & Anderson, G. J. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-382026-6.00071-3 · Cited by 22
Villaño, D., Vilaplana, C., Medina, S., Algaba‐Chueca, F., Cejuela-Anta, R., Sanz, J. M. M., Ferreres, F., & Gil‐Izquierdo, Á. (2016) · Molecules · doi:10.3390/molecules21101333 · Cited by 25
“It has also been shown that hepcidin is regulated by hemojuvelin, a protein produced in the liver and whose gene expression is responsible for juvenile hemochromatosis, causing excessive accumulation of iron in different organs, mainly in the liver [2], and promoting the development of certain infectious diseases [3].”
Pagani, A., Colucci, S., Bocciardi, R., Bertamino, M., Dufour, C., Ravazzolo, R., Silvestri, L., & Camaschella, C. (2017) · Blood · doi:10.1182/blood-2017-03-773481 · Cited by 23
“The BMP-coreceptor HJV is essential for hepcidin activation (19) and accordingly, its overexpression in hepatoma cells upregulates hepcidin (Figure 1D).”
Background
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
