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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.
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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]
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“…al., 2005; Nemeth et al., 2005), Hemojuvelin (HJV ; Lanzara et al., 2004; Papanikolaou et al., 2004; Huang et al., 2005; Niederkofler et al., 2005; Babitt et al., 2006) or Hepcidin itself (Roetto et al., 2003; Lesbordes-Brion et al., 2006), and/or ferroportin (Pietrangelo, 2004; Sham et al.,…”
BackgroundInfluentialPoli, M., Asperti, M., Ruzzenenti, P., Mandelli, L., Campostrini, N., Martini, G., Somma, M. D., Maccarinelli, F., Girelli, D., Naggi, A., et al. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.09.007 · Cited by 47
Monomeric gremlin is a novel vascular endothelial growth factor receptor-2 antagonist
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“BMP antagonists bind to and sequester BMPs in inactive complexes, preventing their interaction with cognate receptors and the transcription of various BMPdependent genes, including hepcidin [27].”
BackgroundMitochondrial damage and iron metabolic dysregulation in hepatitis C virus infection
Hino, K., Nishina, S., Sasaki, K., & Hara, Y. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.044 · Cited by 49
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“Studies by Ikeda et al. showed that the female sex hormone estrogen stimulates hepcidin expression in a GPR30-BMP6-dependent manner [69].”
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“Several reports have concluded that all three RGM proteins when expressed on the cell membrane can function as putative BMP coreceptors and can enhance BMP-stimulated activation of promoter-reporter genes (2, 4, 36, 46).”
BackgroundInfluentialHepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection
Wang, H.-Z., He, Y.-X., Yang, C.-J., Zhou, W., & Zou, C.-G. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1101436 · Cited by 44
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“(37,38) However, exogenously added homodimeric BMP2 and BMP6 ligand can stimulate hepcidin expression both in vitro and in vivo.(12,39) Future studies will be needed to understand why endogenous BMP6 and BMP2 fail to appreciably compensate for the loss of the other in endothelial Bmp2 and Bmp6 KO mice.”
BackgroundGDF-5 can act as a context-dependent BMP-2 antagonist
Klammert, U., Mueller, T. D., Hellmann, T. V., Wuerzler, K. K., Kotzsch, A., Schliermann, A., Schmitz, W., Kuebler, A. C., Sebald, W., & Nickel, J. (2015) · BMC Biology · doi:10.1186/s12915-015-0183-8 · Cited by 45
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BackgroundThe global burden of iron overload
Wood, M. J., Skoien, R., & Powell, L. W. (2009) · Hepatology International · doi:10.1007/s12072-009-9144-z · Cited by 45
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“Notably, HFE, TFR2, and HJV mutations are also associated with reduced hepatic SMAD1/5/8 signaling,(8-11,36) raising the hypothesis that deficient SMAD1/5/8 signaling could contribute to the pathophysiology of liver disease in human patients with hereditary hemochromatosis.”
BackgroundIron Deficiency in Pulmonary Arterial Hypertension: A Deep Dive into the Mechanisms
Quatredeniers, M., Mendes‐Ferreira, P., Santos‐Ribeiro, D., Nakhleh, M. K., Ghigna, M., Cohen‐Kaminsky, S., & Perros, F. (2021) · Cells · doi:10.3390/cells10020477 · Cited by 45
“HJV acts as a co-receptor for the BMP receptor complexes and is required for the full upregulation of hepcidin expression by BMP6 [28].”
BackgroundInfluentialManaging the Dual Nature of Iron to Preserve Health
Silvestri, L., Pettinato, M., Furiosi, V., Volpe, L. B., Nai, A., & Pagani, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043995 · Cited by 49
“Molecularly, hepcidin expression in hepatocytes is regulated by the bone morphogenetic protein (BMP)-Son-of-Mother Against Decapentaplegic (SMAD) pathway [47] (Figure 3B), a signaling pathway involved in crucial biological processes, such as bone formation, development, inflammation, neuronal function, etc.”
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Harrison-Findik, D.-D. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.1186 · Cited by 56
Iron Metabolism and Inflammatory Mediators in Patients with Renal Dysfunction
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“In contrast, protein-bound low-molecular-weight compounds, due to their strong binding with abundant serum proteins like albumin, are not readily removed by current dialysis techniques, regardless of membrane pore size [86,87].”
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“Pharmacologic modulators of BMP6–HJV–SMAD affect hepcidin expression and systemic iron homeostasis in vivo.”
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“Antibodies were validated in prior publications (2) or using siRNA knockdown experiments (data not shown).”
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“This effect might be initiated by renal inflammation and is thought to limit iron efflux from cells, promoting intracellular iron retention (Babitt et al. 2006).”
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Neogenin-mediated Hemojuvelin Shedding Occurs after Hemojuvelin Traffics to the Plasma Membrane
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Poggiali, E., Andreozzi, F., Nava, I., Consonni, D., Graziadei, G., & Cappellini, M. D. (2014) · American Journal of Hematology · doi:10.1002/ajh.23929 · Cited by 41
“Several factors contribute to the regulation of hepcidin synthesis: the bone morphogenetic proteins (BMPs)—hemojuvelin (HJV) complex [7] and the interleukin-6—signal transducer and activator of transcription pathway [6] increase hepcidin synthesis, while matriptase-2 down regulates hepcidin synthesis.”
BackgroundPerucca, S., Palma, A. D., Piccaluga, P. P., Gemelli, C., Zoratti, E., Bassi, G., Giacopuzzi, E., Lojacono, A., Borsani, G., Tagliafico, E., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172430 · Cited by 41
Balance of cardiac and systemic hepcidin and its role in heart physiology and pathology
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Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload
Spasić, M. V., Sparla, R., Mleczko‐Sanecka, K., Migas, M. C., Breitkopf‐Heinlein, K., Dooley, S., Vaulont, S., Fleming, R. E., & Muckenthaler, M. U. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.08.013 · Cited by 44
“2C, 3A,C), being consistent with previous reports [8,10,11,13,14].”
ResultThe RGM protein DRAG-1 positively regulates a BMP-like signaling pathway inCaenorhabditis elegans
Tian, C., Sen, D., Shi, H., Foehr, M. L., Plavskin, Y., Vatamaniuk, O. K., & Liu, J. (2010) · Development · doi:10.1242/dev.051615 · Cited by 41
“In particular, a family of repulsive guidance molecules (RGMs) has recently been found to bind different BMPs with high affinity and act as BMP coreceptors in tissue culture experiments (Samad et al., 2005; Babitt et al., 2005; Babitt et al., 2006).”
BackgroundInfluentialHepcidin is a Potential Regulator of Iron Status in Chronic Kidney Disease
Tsuchiya, K., & Nitta, K. (2012) · Therapeutic Apheresis and Dialysis · doi:10.1111/1744-9987.12001 · Cited by 42
“The BMP receptor, hemojuvelin (HJV), is crucial for hepcidin expression, because various hepcidin regulatory pathways converge at this membrane-bound protein (25).”
BackgroundThe hepcidin circuits act: Balancing iron and inflammation
Maliken, B. D., Nelson, J. E., & Kowdley, K. V. (2011) · Hepatology · doi:10.1002/hep.24267 · Cited by 40
Hemojuvelin: A New Link Between Obesity and Iron Homeostasis
Luciani, N., Brasse‐Lagnel, C., Poli, M., Anty, R., Lesueur, C., Cormont, M., Laquerrière, A., Folope, V., MARCHAND‐BRUSTEL, Y. L., Gugenheim, J., et al. (2011) · Obesity · doi:10.1038/oby.2011.12 · Cited by 43
“After translocation into the nucleus, this complex regulates positively hepcidin expression in vitro (15,16) and in vivo (17).”
BackgroundInfluentialMolecular pathogenesis and clinical consequences of iron overload in liver cirrhosis
Sikorska, K., Bernat, A., & Wróblewska, A. (2016) · Hepatobiliary & pancreatic diseases international · doi:10.1016/s1499-3872(16)60135-2 · Cited by 41
Advances in understanding iron metabolism and its crosstalk with erythropoiesis
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Hepcidin as a therapeutic target for anemia and inflammation associated with chronic kidney disease
Małyszko, J., Małyszko, J. S., & Matuszkiewicz‐Rowińska, J. (2019) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2019.1599358 · Cited by 40
“Bone morphogenetic protein receptor (BMPR)/ hemojuvelin/SMAD (Small Mothers Against Decapentaplegic) signaling pathway is the major pathway inducing expression of hepcidin [16,17].”
BackgroundKuninger, D., Kuns-Hashimoto, R., Nili, M., & Rotwein, P. S. (2008) · BMC Biochemistry · doi:10.1186/1471-2091-9-9 · Cited by 41
“Recent studies have suggested that membrane-associated RGMc increases hepcidin gene expression in the liver by collaboration with signaling pathways activated by bone morphogenic proteins (BMP) 2 and 4 [18,19], and thus acts to prevent iron import.”
BackgroundActivated macrophages induce hepcidin expression in HuH7 hepatoma cells
Matak, P., Chaston, T. B., Chung, B., Srai, S. K., McKie, A. T., & Sharp, P. (2009) · Haematologica · doi:10.3324/haematol.2008.003400 · Cited by 40
Altered hepatic BMP signaling pathway in human HFE hemochromatosis
Bolondi, G., Garuti, C., Corradini, E., Zoller, H., Vogel, W., Finkenstedt, A., Babitt, J. L., Lin, H. Y.-F., & Pietrangelo, A. (2010) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2010.08.010 · Cited by 41
“In order to verify whether in human HC the BMP post-receptor signaling pathway is impaired as recently reported in mouse HC [25; 26], we investigated the expression of two known intracellular targets of BMPs, SMAD7 and Id1 [5] [7] in our HC patients and control groups.”
Regulation of cellular iron metabolism and its implications in lung cancer progression
Xiong, W., Wang, L., & Yu, F. (2014) · Medical Oncology · doi:10.1007/s12032-014-0028-2 · Cited by 39
“The BMP pathway with its canonical signaling system utilizing cytoplasmic Smads is the key pathway for the regulation of hepcidin transcription [57].”
BackgroundPadda, R. S., Gkouvatsos, K., Guido, M., Mui, J., Vali, H., & Pantopoulos, K. (2014) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00137.2014 · Cited by 40
“This disease is a rare variant of HH that is caused by functional inactivation of HJV (28), a bone morphogenetic protein (BMP) coreceptor that enhances iron-dependent signaling to hepcidin via the BMP/mothers against decapentaplegic pathway (1).”
Knockout Mouse Models of Iron Homeostasis
Fleming, R. E., Qi, F., & Britton, R. S. (2011) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-072610-145117 · Cited by 39
Genetic variability of TMPRSS6 and its association with iron deficiency anaemia
Delbini, P., Vaja, V., Graziadei, G., Duca, L., Nava, I., Refaldi, C., & Cappellini, M. D. (2010) · British Journal of Haematology · doi:10.1111/j.1365-2141.2010.08349.x · Cited by 38
“Matriptase-2 represses hepcidin expression by cleaving membrane-bound hemojuvelin (m-HJV) (Silvestri et al, 2008), the bone morphogenetic protein (BMP) coreceptor, thereby reducing signalling through the SMAD proteins pathway (Babitt et al, 2006).”
BackgroundStimulating neuroregeneration as a therapeutic drug approach for traumatic brain injury
Mueller, B. K., Mueller, R., & Schoemaker, H. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00220.x · Cited by 38
“In addition, all RGM proteins have been shown to interact with bone morphogenetic proteins (BMP) 2 and 4 (Babitt et al., 2005; 2006; Samad et al., 2005) and early data suggest that BMP interaction with RGM A also results in neurite growth inhibition.”
BackgroundImplications of Malaria On Iron Deficiency Control Strategies
Spottiswoode, N., Fried, M., Drakesmith, H., & Duffy, P. E. (2012) · Advances in Nutrition · doi:10.3945/an.111.001156 · Cited by 38
“Hepcidin serves to maintain iron homeostasis by decreasing the amount of biologically available iron (44,45).”
Pandur, E., Tamási, K., Pap, R., Varga, E., Miseta, A., & Sipos, K. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00694-4 · Cited by 37
Fisher, A. L., & Babitt, J. L. (2021) · Developmental Dynamics · doi:10.1002/dvdy.372 · Cited by 41
“Similar to other RGM-proteins, HJV acts as a coreceptor that binds directly to BMP ligands and enhances BMP signaling in cultured hepatocytes.(39) HJV binds with high affinity to BMP2, 4, 5, 6, and 7, but has the highest affinity for class II BMP ligands (BMP5,6,7)(190) among the RGM proteins, consistent with the role…”
BackgroundInfluentialIron metabolism meets signal transduction
Anderson, G. J., & Frazer, D. M. (2006) · Nature Genetics · doi:10.1038/ng0506-503 · Cited by 37
Inherited metabolic disease of the liver
Taddei, T. H., Mistry, P. K., & Schilsky, M. L. (2008) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e3282fcbc0f · Cited by 38
Hepcidin Activation During Inflammation: Make It STAT
Fleming, R. E. (2007) · Gastroenterology · doi:10.1053/j.gastro.2006.11.049 · Cited by 36
Mayeur, C., Kolodziej, S. A., Wang, A., Xu, X., Lee, A., Yu, P. B., Shen, J., Bloch, K. D., & Bloch, D. B. (2015) · Haematologica · doi:10.3324/haematol.2014.111484 · Cited by 38
“Bone morphogenetic protein (BMP) signaling induces transcription of the gene encoding hepcidin (HAMP).(3) Activation of the BMP pathway induces the phosphorylation of regulatory SMAD proteins (SMADs 1, 5, and 8), which activate the expression of target genes, such as the genes encoding the inhibitor of DNA binding 1 (…”
BackgroundIron as a therapeutic target in chronic liver disease
Kouroumalis, E., Tsomidis, I., & Voumvouraki, A. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i4.616 · Cited by 42
Hereditary hemochromatosis and transferrin receptor 2
Chen, J., & Enns, C. A. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.07.015 · Cited by 38
“Mice fed high iron diets show increased SMAD1/5/8 phosphorylation [45, 46] Chen and Enns Page 2”
BackgroundLenoir, A., Deschemin, J., Kautz, L., Ramsay, A. J., Roth, M., López-Otı́n, C., Vaulont, S., & Nicolas, G. (2010) · Blood · doi:10.1182/blood-2010-07-295147 · Cited by 37
Neogenin Facilitates the Induction of Hepcidin Expression by Hemojuvelin in the Liver
Zhao, N., Maxson, J. E., Zhang, R. H., Wahedi, M., Enns, C. A., & Zhang, A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.721191 · Cited by 37
“We generated a FLAG-tagged Hjv construct using the same strategy as described for human HJV (9).”
MethodTGF-β Family Signaling in Ductal Differentiation and Branching MorphogenesisPreprint
Kahata, K., Maturi, V., & Moustakas, A. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a031997 · Cited by 38
“In addition, BMP signaling, mediated by GPI-anchored coreceptors of the repulsive guidance molecule (RGM) family, regulates normal iron homeostasis in the liver (Babitt et al. 2006).”
BackgroundIron effects versus metabolic alterations in hereditary hemochromatosis driven bone loss
Baschant, U., Altamura, S., Steele-Perkins, P., Muckenthaler, M. U., Spasić, M. V., Hofbauer, L. C., Steinbicker, A. U., & Rauner, M. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.06.004 · Cited by 37
Iron metabolic disorder in chronic hepatitis C : Mechanisms and relevance to hepatocarcinogenesis
Hino, K., Nishina, S., & Hara, Y. (2013) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12243 · Cited by 35
Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting
Zhang, P., He, J., Wang, F., Gong, J., Wang, L., Wu, Q., Li, W., Liu, H., Wang, J., Zhang, K., et al. (2019) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12414 · Cited by 36
“functions as a coreceptor for BMPs in the liver and enhances classical BMP signalling.(18,22,23) The absence of Hjv results in the reduced expression of phosphorylated Smad1/5/8 in the Hjv / liver.”
BackgroundInfluentialHepcidin and Iron Metabolism in Experimental Liver Injury
Bloomer, S. A., & Brown, K. E. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.04.005 · Cited by 38
“This process is achieved by the binding of specific BMPs to BMP type II receptors, which phosphorylate BMP type I receptors, activating the SMAD 1/5/8 pathway and leading to the formation of a heteromeric complex with Smad4 that translocates to the nucleus to stimulate hepcidin gene expression.(10,11) BMPs appear to m…”
BackgroundBlood Iron Homeostasis: Newly Discovered Proteins and Iron Imbalance
Bleackley, M. R., Wong, A. Y. K., Hudson, D. M., Wu, C., & MacGillivray, R. T. A. (2009) · Transfusion Medicine Reviews · doi:10.1016/j.tmrv.2008.12.001 · Cited by 38
Shanmugam, N. K. N., Ellenbogen, S., Trebicka, E., Wang, L., Mukhopadhyay, S., Lacy‐Hulbert, A., Gallini, C. A., Garrett, W. S., & Cherayil, B. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038136 · Cited by 37
“In some experiments, the cells were transiently transfected with a firefly luciferase reporter driven by the human hepcidin promoter [25] using Lipofectamine 2000 (Life Technologies, Grand Island, NY), along with a constitutively expressed Renilla luciferase reporter.”
MethodSchaefer, B., Haschka, D., Finkenstedt, A., Petersen, B.-S., Theurl, I., Henninger, B., Janecke, A. R., Wang, C.-Y., Lin, H. Y., Veits, L., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv348 · Cited by 35
Böser, P., Seemann, D., Liguori, M. J., Fan, L., Huang, L., Hafner, M., Popp, A., & Mueller, B. K. (2015) · The AAPS Journal · doi:10.1208/s12248-015-9770-4 · Cited by 35
“reduced liver hepcidin expression (6, 7) suggesting that they jointly regulated the BMP/Smad-mediated signaling pathway of hepcidin regulation (8).”
BackgroundRepulsive guidance molecules (RGMs) and neogenin in bone morphogenetic protein (BMP) signaling
Tian, C., & Liu, J. (2013) · Molecular Reproduction and Development · doi:10.1002/mrd.22199 · Cited by 35
“Fc directly binds to (125)I-BMP2 and (125)I-BMP4, and this binding can be competed away by an excess of unlabeled BMP2 and BMP4, but not by BMP7 or TGFb1 (Babitt et al., 2006).”
InfluentialProcessing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells
Maxson, J. E., Enns, C. A., & Zhang, A. (2008) · Blood · doi:10.1182/blood-2008-08-174565 · Cited by 35
Li, P., Zhang, G., Li, J., Yang, R., Chen, S., Wu, S., Zhang, F., Bai, Y., Zhao, H., Wang, Y., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150790 · Cited by 35
RetractedBöttcher‐Friebertshäuser, E. (2018) · Springer eBooks · doi:10.1007/978-3-319-75474-1_8 · Cited by 35
“Hemojuvelin is a coreceptor in the bone morphogenetic protein (BMP)/SMAD signaling pathway that upregulates hepcidin in response to increased iron (Babitt et al.”
BackgroundKartikasari, A. E. R., Roelofs, R., Schaeps, R. M. J., Kemna, E., Peters, W. H. M., Swinkels, D. W., & Tjalsma, H. (2008) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2008.08.004 · Cited by 35
“Several cytokines including IL-6 and BMPs have been shown to promote HAMP expression in hepatocytes at transcriptional level [8,10,12,15,16,18], however the levels of secreted bioactive protein are not known.”
BackgroundHemojuvelin: The Hepcidin Story Continues
Małyszko, J. (2009) · Kidney & Blood Pressure Research · doi:10.1159/000208988 · Cited by 35
Nili, M., Shinde, U. P., & Rotwein, P. S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.130286 · Cited by 37
Pelucchi, S., Mariani, R., Trombini, P., Coletti, S., Pozzi, M., Paolini, V., Barisani, D., & Piperno, A. (2009) · Haematologica · doi:10.3324/haematol.13576 · Cited by 35
“TFR2 functions upstream of SMAD4 in activating the HAMP promoter, perhaps through an independent signal or by affecting signal transduction by the BMP receptors.(5,8) Interestingly, HJV and, to a lesser extent, BMP2 transcripts were also markedly reduced suggesting an interaction between TFR2 and HJV in the regulation…”
BackgroundHepcidin regulation by BMP signaling in macrophages is lipopolysaccharide dependent
Wu, X., Yung, L.-M., Cheng, W.-H., Yu, P. B., Babitt, J. L., Lin, H. Y., & Xia, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044622 · Cited by 34
“Conversely, inhibition of BMP signaling through genetic deletion of the ligand BMP6 [11]; [15], the BMP type I receptor ALK3 [16], the BMP co-receptor hemojuvelin (Hjv) [7], or Smad4 [8], or through administration of BMP ligand antagonists HJV.”
BackgroundTroadec, M., Lainé, F., Daniel, V., Rochcongar, P., Ropert, M., Cabillic, F., Perrin, M., Morçet, J., Loréal, O., Olbina, G., et al. (2009) · European Journal of Applied Physiology · doi:10.1007/s00421-009-1031-8 · Cited by 34
“HJV, located in the hepatocyte membrane, induces hepatic hepcidin expression through bone morphogenetic protein (BMP)-mediated signaling (Babitt et al. 2006) whereas the soluble form of HJV has the opposite eVect on hepcidin expression.”
BackgroundMolecular perspective of iron uptake, related diseases, and treatments
Shokrgozar, N., & Golafshan, H. (2019) · Blood Research · doi:10.5045/br.2019.54.1.10 · Cited by 37
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
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