The DOI matches its Crossref record; 35 of the 36 references it cites were found in a registry or an index.
Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis
Open accessAbstract
The liver peptide hepcidin regulates iron absorption and recycling. Hemojuvelin (HJV) has a key role in hepcidin regulation, and its inactivation causes severe iron overload both in humans and in mice. Membrane HJV (m-HJV) acts as a coreceptor for bone morphogenetic proteins (BMPs), whereas soluble HJV (s-HJV) may down-regulate hepcidin in a competitive way interfering with BMP signaling. s-HJV is decreased by iron in vitro and increased by iron deficiency in vivo. However, the mechanisms regulating the 2 HJV isoforms remain unclear. Here we show that s-HJV originates from a furin cleavage at position 332-335. s-HJV is reduced in the cleavage mutant R335Q as well as in cells treated with a furin inhibitor, and increased in cells overexpressing exogenous furin, but not in cells overexpressing an inactive furin variant. Furin is up-regulated by iron deficiency and hypoxia in association with the stabilization of HIF-1alpha. Increased s-HJV in response to HIF-1alpha occurs during differentiation of murine muscle cells expressing endogenous Hjv. Our data are relevant to the mechanisms that relate iron metabolism to the hypoxic response. The release of s-HJV might be a tissue-specific mechanism, signaling the local iron requests of hypoxic skeletal muscles independently of the oxygen status of the liver.
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“In hypoxia hepcidin is also suppressed in vitro by soluble hemojuvelin, released by furin,53 an effect unclear in vivo, and by platelet-derived growth factor-BB in volunteers exposed to hypoxia.54”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [53]
In the citing paper
“Recent in vivo studies have shown that HIF induces furin, a proprotein convertase that cleaves HJV and generates a soluble form of HJV, which suppresses hepcidin by antagonizing BMP6 signaling.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [203]
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Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation
Ganz, T. (2003) · Blood · doi:10.1182/blood-2003-03-0672 · Cited by 1,544
HIF-1 and mechanisms of hypoxia sensing
Semenza, G. L. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00194-0 · Cited by 1,301
Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
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., et al. (2006) · Nature Genetics · doi:10.1038/ng1777 · Cited by 1,026
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
Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)
Peyssonnaux, C., Zinkernagel, A. S., Schuepbach, R. A., Rankin, E., Vaulont, S., Haase, V. H., Nizet, V., & Johnson, R. S. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31370 · Cited by 639
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
ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins
Puntervoll, P. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg545 · Cited by 597
Prediction of proprotein convertase cleavage sites
Duckert, P., Brunak, S., & Blom, N. (2004) · Protein Engineering Design and Selection · doi:10.1093/protein/gzh013 · Cited by 583
Wittenberg, J. B., & Wittenberg, B. A. (2003) · Journal of Experimental Biology · doi:10.1242/jeb.00243 · Cited by 550
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
Self-citationGanz, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00008.2013 · Cited by 1,122
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787
Iron metabolism and iron disorders revisited in the hepcidin era
Camaschella, C., Nai, A., & Silvestri, L. (2020) · Haematologica · doi:10.3324/haematol.2019.232124 · Cited by 734
Self-citationIron Overload in Human Disease
Fleming, R. E., & Ponka, P. (2012) · New England Journal of Medicine · doi:10.1056/nejmra1004967 · Cited by 607
Metadata
- Authors
- Silvestri, L., Pagani, A., & Camaschella, C.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-01-15
- Volume
- 111
- Issue
- 2
- Pages
- 924-931
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2005438156
- Cited by
- 311
- References
- 36
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 11 · 2023: 3 · 2022: 10 · 2021: 18 · 2020: 12 · 2019: 16 · 2018: 16 · 2017: 16 · 2016: 13 · 2015: 17 · 2014: 16 · 2013: 27 · 2012: 20
- FWCI
- 17.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- hemojuvelin, furin, proteolytic cleavage, hypoxia, iron homeostasis, hepcidin, HIF-1α, iron deficiency, BMP signaling, skeletal muscle, myogenesis, iron overload
- MeSH terms
- Hemochromatosis Protein, Iron Deficiencies, Animals, Cell Differentiation, HeLa Cells, Homeostasis, Humans, Iron, Liver, Membrane Proteins, Organ Specificity, Oxygen, Signal Transduction, Down-Regulation, Cell Hypoxia, Muscle, Skeletal, Iron Overload, Bone Morphogenetic Proteins, Amino Acid Substitution, Protein Isoforms, Mutation, Missense, Antimicrobial Cationic Peptides, Muscle Cells, Furin, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, GPI-Linked Proteins, Hepcidins
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