Affinage

HJV

Hemojuvelin · UniProt Q6ZVN8

Length
426 aa
Mass
45.1 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Hemojuvelin (HJV) is a GPI-anchored membrane co-receptor that functions in hepatocytes to control systemic iron homeostasis by enhancing bone morphogenetic protein (BMP) signaling that drives transcription of the iron hormone hepcidin (PMID:16604073, PMID:21748766, PMID:21493799). Membrane-bound HJV potentiates BMP-mediated phosphorylation of SMAD1/5/8 and upregulates hepcidin, and HJV mutants linked to juvenile hemochromatosis lose this signaling capacity; Hjv-deficient mice and hepatocytes show severely blunted BMP-induced hepcidin and consequent iron overload (PMID:16604073, PMID:16075058). HJV selectively engages BMP-2, BMP-4, and BMP-6 as ligands and assembles with type II receptors ActRIIA and BMPRII and type I receptors ALK2/ALK3/ALK6 to relay signal onto conserved BMP-responsive elements in the hepcidin promoter (PMID:18326817, PMID:19229506). Tissue-specific knockouts establish that hepatic—not muscle—HJV is necessary and sufficient for iron regulation, and reconstitution of HJV in hepatocytes restores hepcidin and phospho-SMAD signaling chiefly by potentiating BMP6 (PMID:21748766, PMID:21493799, PMID:20363739). The transmembrane protein neogenin binds HJV and is required in vivo for HJV iron-regulatory function, scaffolding the BMP signaling complex through association with ALK3 and via Hjv-triggered cleavage of the neogenin cytoplasmic domain (PMID:19564337, PMID:27072365, PMID:33824974). HJV abundance and signaling output are tuned by regulated shedding: proprotein convertase furin cleaves HJV at a polybasic RNRR site to release a soluble decoy form that suppresses hepcidin, whereas the serine protease matriptase-2 (TMPRSS6) cleaves HJV at distinct arginine residues to inhibit hepcidin activation, with neogenin facilitating both surface trafficking and matriptase-2 cleavage (PMID:18976966, PMID:17869549, PMID:20937842, PMID:22893705). Iron status governs this balance, with iron loading retaining membrane HJV and suppressing release of soluble forms (PMID:15998830, PMID:17869549, PMID:17264300). HFE and TfR2 form a multi-protein membrane complex with HJV, and genetic epistasis places HFE and HJV in a common hepcidin-regulatory pathway (PMID:22728873, PMID:25609138, PMID:25608116). In skeletal muscle, HJV instead acts as a co-receptor for TGF-β receptor II, suppressing TGF-β1/Smad3 signaling and muscle atrophy, a function mechanistically distinct from its hepatic BMP role (PMID:30884219).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2005 High

    Establishing that HJV is a GPI-anchored protein physically partnering with neogenin answered how this membrane protein is presented and what its first binding partner is.

    Evidence Stable HJV transfection, reciprocal Co-IP, GPI-anchor and iron-accumulation assays in HEK293 cells

    PMID:16103117

    Open questions at the time
    • Functional consequence of neogenin binding for hepcidin not yet defined
    • Did not link HJV to BMP signaling
  2. 2005 High

    Distinguishing membrane HJV (which raises hepcidin) from soluble HJV (which suppresses it) and showing iron inhibits shedding framed HJV as an iron-responsive competitive regulator.

    Evidence siRNA knockdown, recombinant soluble HJV treatment of primary hepatocytes, iron titration

    PMID:15998830

    Open questions at the time
    • Protease responsible for shedding unknown
    • Molecular target of soluble HJV not identified
  3. 2005 High

    Hjv-mutant mice with iron overload and low hepcidin established HJV as a genetically essential upstream regulator of hepcidin, separate from inflammatory pathways.

    Evidence Hjv-mutant mouse, expression analysis, LPS inflammation model

    PMID:16075058

    Open questions at the time
    • Molecular signaling pathway not resolved
    • Cell-autonomous vs systemic contribution untested
  4. 2006 High

    Identifying HJV as a BMP co-receptor that upregulates hepcidin defined its core molecular mechanism and connected disease mutations to signaling defects.

    Evidence BMP signaling and luciferase reporter assays, Hfe2-/- hepatocytes, mutant analysis

    PMID:16604073

    Open questions at the time
    • Specific BMP ligands and receptors not yet enumerated
    • Role of neogenin in signaling unclear
  5. 2006 Medium

    Characterizing the complex biosynthesis of HJV into a disulfide-linked heterodimer and basolateral localization with TfR2 began to define how the active membrane species is generated and positioned.

    Evidence Pulse-chase, cell-surface labeling, glycosylation analysis, immunofluorescence in muscle cells and liver tissue

    PMID:16868025 PMID:16932966

    Open questions at the time
    • Functional role of heterodimer in signaling untested
    • TfR2 co-localization not yet shown to be a direct interaction
  6. 2007 Medium

    Mapping furin cleavage at the RNRR site and showing neogenin and holo-transferrin regulate shedding identified the proteolytic and iron-sensing controls on soluble HJV production.

    Evidence PC inhibitors, RNRR-site mutagenesis, neogenin siRNA/overexpression, holo-Tf dose-response, in vivo iron-deficient rat

    PMID:17331953 PMID:17869549

    Open questions at the time
    • Whether furin product is the physiological decoy in vivo unresolved
    • Mechanism by which neogenin promotes shedding not defined
  7. 2007 Medium

    Showing holo-transferrin stimulates hepcidin through an HJV/BMP2/4-dependent route, while BMP9 acts independently of HJV, clarified which ligand axes route through HJV.

    Evidence Primary murine hepatocytes, holo/apo-transferrin treatment, pathway inhibition, siRNA

    PMID:17540841

    Open questions at the time
    • Direct link between transferrin sensing and HJV not biochemically defined
    • Single primary-hepatocyte system
  8. 2008 High

    Identifying matriptase-2 (TMPRSS6) as a protease that cleaves membrane HJV to suppress hepcidin defined a key negative regulatory enzyme of the pathway.

    Evidence Cleavage assays, MASK active-site mutant, Co-IP interaction mapping, zebrafish in vivo model

    PMID:18976966

    Open questions at the time
    • Exact cleavage residues not yet mapped
    • Functional properties of the soluble product not characterized
  9. 2008 High

    Systematically defining HJV's BMP ligand (BMP-2/4/6) and receptor (ActRIIA, BMPRII, ALK2/3/6) selectivity built the receptor-level architecture of HJV-enhanced signaling.

    Evidence BMP ligand binding and receptor co-transfection signaling in hepatoma cells, neogenin siRNA, hepcidin reporters

    PMID:18326817

    Open questions at the time
    • Stoichiometry of the receptor complex not determined
    • Apparent dispensability of neogenin here conflicts with later in vivo data
  10. 2008 Medium

    Biochemical mapping showed neogenin binds HJV via its membrane-proximal FNIII domains and that BMP-2 and neogenin can engage HJV simultaneously, supporting a multiprotein signaling complex.

    Evidence Recombinant protein binding assays, neogenin domain-deletion mapping, affinity measurements

    PMID:18335997

    Open questions at the time
    • In vivo relevance of simultaneous binding not tested here
    • Affinities of competing interactions not ranked
  11. 2008 Medium

    Resolving HJV trafficking — Golgi retrograde routing, neogenin-dependent dynamin-independent endocytosis, and ER retention of disease mutants — explained how mutations cause juvenile hemochromatosis and how soluble HJV is generated.

    Evidence Oligosaccharide (Endo H/PNGase F) analysis, neogenin siRNA, cholesterol/dynamin/lysosome inhibitors, mutant expression in HeLa/HepG2

    PMID:17264300 PMID:18384687 PMID:18445598 PMID:19029439

    Open questions at the time
    • Precise sequence of cleavage and trafficking steps still partly inferred
    • Single-lab trafficking conclusions
  12. 2008 Medium

    Mapping disease-mutant defects to either impaired BMP-2 binding or impaired neogenin binding showed that distinct mutations disrupt distinct molecular interactions of HJV.

    Evidence BMP-2 and cell-surface neogenin binding assays for wild-type and mutant HJV

    PMID:18287331

    Open questions at the time
    • Functional hepcidin output of each mutant not measured here
    • In vivo correlation lacking
  13. 2009 Medium

    Dissecting two BMP-responsive elements in the hepcidin promoter and showing neogenin is required for robust HJV-dependent hepcidin induction connected receptor signaling to the transcriptional output and elevated neogenin to an essential cofactor.

    Evidence Hepcidin promoter reporter mutagenesis, neogenin siRNA in HepG2, in vivo soluble neogenin fragment in mice

    PMID:19229506 PMID:19564337

    Open questions at the time
    • Conflict with prior report that neogenin was dispensable for signaling
    • SMAD occupancy of BMP-REs not directly shown
  14. 2010 Medium

    In vivo neogenin-mutant mice and matriptase-2 cleavage-site mapping refined neogenin as a surface stabilizer of HJV and showed the matriptase-2 product is functionally distinct from the furin decoy.

    Evidence Neogenin mutant mice, HJV secretion assays, HJV Arg-residue mutagenesis, BMP6 binding and hepcidin readouts

    PMID:20065295 PMID:20937842

    Open questions at the time
    • Exact cleavage residue not unified across studies
    • Relative in vivo contribution of furin vs matriptase-2 products unresolved
  15. 2010 High

    Tissue-specific knockout and AAV reconstitution established that hepatic HJV is necessary and sufficient for iron homeostasis, acting principally by potentiating BMP6 signaling.

    Evidence Liver- and muscle-specific Hjv knockout mice, AAV2/8 hepatocyte reconstitution in Hjv-/-, hepcidin and phospho-Smad readouts

    PMID:20363739 PMID:21493799 PMID:21748766

    Open questions at the time
    • Mechanism of muscle HJV not addressed here
    • BMP6 mRNA regulation found independent of HJV, leaving the sensing input upstream of HJV open
  16. 2012 Medium

    Demonstrating an HFE–TfR2–HJV membrane complex and a neogenin–MT2–HJV ternary complex placed HJV within defined multiprotein assemblies for iron sensing and regulated cleavage.

    Evidence Glycerol gradient sedimentation, Co-IP and domain mapping in HuH7; neogenin siRNA, Co-IP, glycan analysis of MT2 cleavage

    PMID:22728873 PMID:22893705

    Open questions at the time
    • Stoichiometry and dynamics of the complexes unknown
    • Single-lab biochemistry
  17. 2015 High

    Double-knockout genetic epistasis placed HFE in the same pathway as HJV and revealed that BMP6 can signal to hepcidin partly independently of HJV, refining the pathway logic.

    Evidence Hfe-/-;Hjv-/- and Hjv-/-;Bmp6-/- double knockout mice, Smad phosphorylation, hepcidin and iron measurements

    PMID:25608116 PMID:25609138 PMID:26406355

    Open questions at the time
    • Molecular basis of HJV-independent BMP6 signaling unresolved
    • Sex-specific differences not mechanistically explained
  18. 2015 Medium

    Mapping TMPRSS6 cleavage to HJV residues 121 and 326 and the role of R121 in heterodimer rearrangement refined the proteolytic processing model of HJV.

    Evidence Arg-to-Ala mutagenesis, TMPRSS6 cleavage assays, N-terminal FLAG fragment analysis, molecular dynamics on RGMb structure

    PMID:25704252

    Open questions at the time
    • Reconciliation with earlier Arg288/Arg774C mapping incomplete
    • In vivo relevance of individual sites untested
  19. 2016 High

    In vivo mutant reconstitution proved that HJV–neogenin and HJV–BMP interactions are both essential, while furin cleavage is dispensable, and linked neogenin to the BMP type I receptor ALK3.

    Evidence Neogenin- and BMP-binding HJV mutants in Hjv-/- mice, neogenin–ALK3 Co-IP, furin-site mutant in vivo, phospho-Smad readouts

    PMID:27072365

    Open questions at the time
    • How neogenin connects HJV to ALK3 mechanistically not fully resolved here
    • Decoy function of soluble HJV not addressed in vivo
  20. 2019 Medium

    Identifying a muscle-specific role for HJV as a TGF-βRII co-receptor that suppresses Smad2/3 signaling revealed a mechanistically distinct, iron-independent function.

    Evidence Conventional and conditional Hjv knockout, mdx and aged-mouse overexpression, HJV–TβRII Co-IP, phospho-Smad2/3, reporter and functional muscle assays

    PMID:30884219

    Open questions at the time
    • Structural basis of HJV–TβRII interaction unknown
    • Relationship to HJV's GPI-anchored processing in muscle unclear
  21. 2021 High

    Hepatocyte-specific neogenin knockout and interaction-disrupting mutants showed neogenin is required in vivo and that HJV binding triggers cleavage of the neogenin cytoplasmic domain to produce a membrane scaffold for BMP signaling.

    Evidence Hepatocyte-specific Neo1 conditional knockout, Neo1-L1046E and Hjv-A183R mutant reconstitution, Co-IP, Neo1 cytoplasmic-domain cleavage analysis

    PMID:33824974

    Open questions at the time
    • Protease cleaving the neogenin cytoplasmic domain not identified
    • How truncated neogenin scaffold engages ALK3/SMAD not fully detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The upstream iron-sensing input that sets the balance between membrane retention and shedding of HJV, and the in vivo physiological weighting of furin versus matriptase-2 cleavage products, remain unresolved.
  • No defined molecular sensor coupling cellular iron to HJV shedding
  • Relative contribution of each soluble HJV species to systemic hepcidin tuning unquantified
  • Structural model of the full HJV–neogenin–BMP receptor complex lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1430728 Metabolism 2
Partners
BMP2BMP6FURINHFENEO1TFR2TGFBR2TMPRSS6
Complex memberships
HFE-TfR2-HJV iron-sensing complexHJV-neogenin-BMP receptor (ALK3) signaling complexneogenin-matriptase-2(TMPRSS6)-HJV ternary complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Hemojuvelin (HJV) functions as a bone morphogenetic protein (BMP) coreceptor that enhances BMP signaling to upregulate hepcidin expression in hepatocytes; HJV mutants associated with hemochromatosis have impaired BMP signaling ability; Hfe2-/- hepatocytes show blunted BMP-induced hepcidin upregulation. BMP signaling assays in transfected cells, Hfe2-/- mouse hepatocyte studies, luciferase reporter assays, phospho-SMAD readouts Nature genetics High 16604073
2005 Cell-associated (membrane) hemojuvelin positively regulates hepcidin mRNA expression independently of the IL-6 pathway, while recombinant soluble hemojuvelin (rs-HJV) suppresses hepcidin mRNA in primary human hepatocytes in a dose-dependent manner; soluble HJV release from cells is inhibited by increasing iron concentrations, suggesting a competitive regulatory mechanism. siRNA knockdown of HJV in hepatocyte cell lines, recombinant soluble HJV treatment of primary human hepatocytes, iron concentration titration experiments Blood High 15998830
2005 HJV is a GPI-anchored protein and undergoes partial autocatalytic cleavage during intracellular processing; HJV co-immunoprecipitates with neogenin but not with DCC; the disease-associated G320V mutant fails to co-immunoprecipitate with neogenin; HJV-induced increase in intracellular iron in HEK293 cells is dependent on the presence of neogenin. Stable transfection of HJV cDNA into HEK293 cells, co-immunoprecipitation, GPI-anchor characterization, transferrin-55Fe accumulation assays, immunoblot The Journal of biological chemistry High 16103117
2005 Hjv-mutant mice exhibit iron overload and a dramatic decrease in hepcidin expression; within the liver, Hjv is selectively expressed by periportal hepatocytes; cytokine-induced inflammation regulates hepcidin expression through an Hjv-independent pathway. Hjv-mutant mouse model, quantitative gene expression analysis, tissue-specific expression by in situ/IHC, LPS-induced inflammation model The Journal of clinical investigation High 16075058
2008 The serine protease matriptase-2 (TMPRSS6) cleaves membrane hemojuvelin, thereby inhibiting hepcidin activation; matriptase-2 lacking its serine protease domain (MASK mutant) shows no cleavage activity; matriptase-2 interacts with HJV through the ectodomain; a disease-associated mutant (R774C) has decreased HJV cleavage capacity. Cleavage assays in transfected cells, domain deletion mutants, interaction mapping by co-immunoprecipitation, zebrafish in vivo model expressing matriptase-2 mutants Cell metabolism High 18976966
2008 HJV selectively uses BMP-2, BMP-4, and BMP-6 as endogenous ligands in hepatoma-derived cell lines; HJV preferentially uses BMP type II receptors ActRIIA and BMPRII but not ActRIIB; HJV enhances utilization of ActRIIA by BMP-2 and BMP-4; HJV can use ALK2, ALK3, and ALK6 as type I receptors in vitro; HJV-induced BMP signaling and hepcidin expression are not altered by neogenin overexpression or inhibition. BMP ligand binding assays, receptor co-transfection/signaling studies in hepatoma cell lines, siRNA knockdown of neogenin, hepcidin reporter assays Blood High 18326817
2007 Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site; this shedding is negatively regulated by both transferrin-bound iron (holo-Tf) and non-transferrin-bound iron (FAC). Proprotein convertase inhibitor studies, site-directed mutagenesis of RNRR cleavage site, iron treatment experiments in cell lines Blood cells, molecules & diseases Medium 17869549
2007 HJV shedding is inhibited by holo-transferrin in a concentration-dependent manner; neogenin mediates HJV shedding — knockdown of neogenin in C2C12 cells suppresses HJV shedding, while neogenin overexpression in HEK293 cells enhances it; BMP4 and its antagonist noggin do not alter HJV shedding, indicating BMP signaling is not involved in this process. siRNA knockdown of neogenin in C2C12 cells, neogenin overexpression in HEK293 cells, holotransferrin dose-response in cell lines, in vivo iron-deficient rat model The Journal of biological chemistry Medium 17331953
2007 Holotransferrin stimulates hepcidin mRNA via a hemojuvelin/BMP2/4-dependent pathway in fresh primary murine hepatocytes; BMP9, while potently increasing basal hepcidin, does not interact with hemojuvelin and its pathway inhibition does not affect iron regulation. Primary murine hepatocyte culture, holotransferrin and apotransferrin treatment, hemojuvelin/BMP pathway inhibition, siRNA knockdown Blood Medium 17540841
2008 Neogenin binds both cleaved and uncleaved hemojuvelin; the hemojuvelin-binding site on neogenin is localized to the membrane-proximal fifth and sixth FNIII domains and juxtamembrane linker; BMP-2 and neogenin can bind simultaneously to hemojuvelin, suggesting a possible multiprotein complex at the hepatocyte membrane. Recombinant protein expression, biochemical binding assays, domain-deletion mapping of neogenin ectodomain, surface plasmon resonance or equivalent binding affinity measurements Biochemistry Medium 18335997
2008 Disease-associated HJV mutants D172E and G320V show reduced BMP-2 binding compared to wild-type; G99V cannot bind BMP-2; neogenin preferentially binds membrane-associated heterodimeric HJV and interacts only with wild-type and G99V on cells, but not D172E or G320V, demonstrating distinct functional defects in different disease-associated mutants. Biochemical BMP-2 binding assays, cell-surface interaction studies with neogenin for wild-type and mutant RGMc/HJV American journal of physiology. Cell physiology Medium 18287331
2006 HJV (RGMc) undergoes complex biosynthesis in skeletal muscle cells: two classes of GPI-anchored and glycosylated RGMc molecules are targeted to the membrane — full-length RGMc is released from the cell surface, while a disulfide-linked heterodimer (N- and C-terminal fragments) is the predominant membrane-associated isoform and is short-lived. The disease-associated G320V mutant does not form the heterodimeric membrane-linked isoform. Pulse-chase studies, cell-surface labeling, glycosylation analysis, immunoblot, mutagenesis of disease-associated G320V variant Journal of cell science Medium 16868025
2007 Several disease-associated HJV mutants (F170S, W191C, G320V) have defective proteolytic processing and are mainly retained in the endoplasmic reticulum rather than being targeted to the cell surface; G99V and C119F reach the cell surface; loss of HJV membrane export is central to juvenile hemochromatosis pathogenesis; membrane HJV level is increased by iron in wild-type mice but not in mutants. Expression of HJV pathogenic mutants in HeLa and HepG2 cells, cell-surface localization assays, biosynthesis/processing analysis, in vivo iron treatment of mice Blood Medium 17264300
2008 HJV undergoes retrograde trafficking to the Golgi before cleavage and release as soluble form; cellular HJV reaches the plasma membrane with high-mannose oligosaccharides (without Golgi processing), while secreted HJV has complex oligosaccharides derived from plasma-membrane HJV; neogenin is required for HJV release but not for its trafficking to the cell surface; HJV release is coupled to neogenin-mediated endocytosis in a dynamin-independent, cholesterol-dependent manner and linked to lysosomal degradation of neogenin. Oligosaccharide analysis (Endo H and PNGase F digestion), neogenin siRNA knockdown, cholesterol depletion with filipin, dynamin inhibition, pulse-chase in HepG2 cells Blood Medium 19029439
2010 Matriptase-2 cleaves HJV at Arg288, producing a soluble form that has decreased ability to bind BMP6 and does not suppress BMP6-induced hepcidin expression; this is functionally distinct from the proprotein convertase cleavage product, which acts as a decoy receptor suppressing BMP signaling. Site-directed mutagenesis of HJV arginine residues, cleavage assays, BMP6 binding assays, hepcidin expression assays The Journal of biological chemistry Medium 20937842
2008 Pro-protein convertases (PCs), specifically furin, are responsible for converting 50 kDa RGMc/HJV to a 40 kDa protein with a truncated C-terminus; a conserved PC recognition and cleavage site in RGMc is not present in RGMA or RGMB; iron loading reduces release of RGMc from the cell membrane and diminishes accumulation of the 40 kDa PC-cleaved species. Cell-permeable and cell-impermeable peptide PC inhibitors, site-directed mutagenesis of PC recognition sequence, in vitro furin cleavage assay, iron treatment of cell cultures BMC biochemistry Medium 18384687
2012 HFE, TfR2, and HJV form a multi-protein membrane complex on the surface of hepatocytes; HFE and TfR2 bind HJV in a non-competitive manner; HJV competes with TfR1 for binding to HFE; residues 120-139 of the TfR2 extracellular domain are critical for binding of both HFE and HJV. Glycerol gradient sedimentation assays, co-immunoprecipitation in transfected HuH7 hepatoma cells, domain-deletion mapping Journal of hepatology Medium 22728873
2009 Neogenin knockdown decreases BMP4-induced hepcidin mRNA levels by 16-fold in HJV-expressing HepG2 cells but only ~2-fold in cells without HJV or expressing the G99V mutant that does not bind BMPs; disruption of the HJV-neogenin interaction markedly suppresses hepcidin expression; in vivo blockade of HJV-neogenin interaction with a soluble neogenin fragment significantly suppresses hepatic hepcidin mRNA in mice. siRNA knockdown of neogenin in HepG2 cells, HJV/neogenin interaction disruption experiments, in vivo mouse injection of soluble neogenin fragment The Journal of biological chemistry Medium 19564337
2010 Neogenin mutant mice exhibit liver iron overload, low hepcidin levels, and reduced BMP signaling; neogenin stabilizes HJV on the cell surface and suppresses HJV secretion; neogenin is expressed in liver cells in a pattern reciprocal to hepcidin expression. Neogenin mutant mouse model, in vitro hepatocyte BMP/Smad signaling assays, HJV secretion assays Blood Medium 20065295
2012 Neogenin interacts with matriptase-2 as well as HJV and facilitates cleavage of HJV by matriptase-2; neogenin is not cleaved by matriptase-2; neogenin knockdown with siRNA increases amounts of both MT2 and HJV on plasma membrane; MT2 cleavage of cell-surface HJV is coupled to a transition from high-mannose to complex oligosaccharides on HJV; neogenin forms a ternary complex with both MT2 and HJV at the plasma membrane. siRNA knockdown of neogenin, co-immunoprecipitation, N-linked oligosaccharide analysis, cell-surface cleavage assays The Journal of biological chemistry Medium 22893705
2009 Two highly conserved BMP-responsive elements (BMP-RE1 at -84/-79 and BMP-RE2 at -2255/-2250) in the hepcidin promoter are critical for basal hepcidin mRNA expression and for hepcidin response to BMP-2 and BMP-6; both elements show additive effects in responding to HJV-mediated BMP signals; only BMP-RE1 is important for hepcidin response to IL-6. Hepcidin promoter reporter assays with BMP-RE1 and BMP-RE2 mutations in hepatoma cells, BMP-2/BMP-6 and HJV transfection, IL-6 stimulation Journal of molecular medicine Medium 19229506
2010 Hepatic ablation of HJV (liver-specific Hjv knockout) results in iron overload quantitatively comparable to ubiquitous Hjv-/- mice, with markedly suppressed hepcidin expression and upregulated BMP6; muscle-specific Hjv ablation is not associated with iron overload or altered hepcidin, demonstrating that hepatic HJV is necessary and sufficient for systemic iron homeostasis. Tissue-specific conditional knockout mice (liver- and muscle-specific), serum/hepatic iron measurements, hepcidin and BMP6 mRNA quantification Hepatology High 21493799 21748766
2010 Expression of HJV in hepatocytes of Hjv-/- mice via AAV2/8 vector increases hepatic hepcidin mRNA by 65-fold and phosphorylated Smad1/5/8 by ~2.5-fold; regulation of hepatic BMP6 mRNA expression by iron is independent of HJV; HJV expression in hepatocytes plays an essential role in hepcidin expression by potentiating BMP6-mediated signaling. AAV-mediated hepatocyte-specific HJV reconstitution in Hjv-/- mice, hepcidin mRNA quantification, phospho-Smad1/5/8 immunoblot, BMP6 mRNA quantification under iron depletion The Journal of biological chemistry High 20363739
2009 Hjv-/- mice fail to mount an appropriate hypoferremic response to acute inflammation (LPS, FSL1, E. coli) because residual hepcidin does not suffice to decrease macrophage ferroportin levels; HJV is required for BMP6/Smad signaling to hepcidin and for synergism between BMP6/Smad and IL-6/Stat pathways; BMP2/Smad signaling to hepcidin is only slightly inhibited by Hjv deficiency. Hjv-/- mouse LPS/infection challenge models, ferroportin immunofluorescence in macrophages, primary hepatocyte BMP2 and BMP6 signaling assays, phospho-Smad readouts Blood High 30213871
2015 In Hjv-/- females, BMP6 can provide a Smad-independent signal adequate to maintain hepcidin at a level sufficient to avoid extrahepatic iron loading; loss of Bmp6 further represses Smad signaling and hepcidin in Hjv-/- mice, demonstrating that BMP6 can signal to hepcidin partly independently of HJV, and that HJV and BMP6 may also operate independently in certain contexts. Hjv-/- x Bmp6-/- double knockout mouse generation and phenotypic analysis, Smad5 phosphorylation, serum hepcidin, organ iron measurements Hepatology High 26406355
2015 Combined disruption of Hfe and Hjv phenocopies single Hjv deficiency with regard to hepcidin suppression, iron overload, and Smad signaling, providing genetic epistasis evidence that Hfe and Hjv operate in the same pathway for hepcidin regulation. Hfe-/- x Hjv-/- double knockout mouse generation, hepcidin mRNA, serum/hepatic iron, Smad signaling analysis under standard and iron-enriched diets Journal of molecular medicine High 25608116 25609138
2016 Neogenin interaction with HJV is critical for the iron-regulatory function of HJV in vivo; a mutation in HJV that reduces neogenin binding dramatically attenuates BMP signaling and hepcidin mRNA when expressed in Hjv-/- mice; neogenin co-immunoprecipitates with ALK3, an essential type-I BMP receptor; HJV-BMP interaction is essential for Hjv stimulation of BMP signaling and hepcidin; furin cleavage of HJV is not required for Hjv stimulation of hepcidin in vivo. Hjv mutation ablating neogenin binding expressed in Hjv-/- mice via liver-targeted vector, co-immunoprecipitation of neogenin with ALK3, furin cleavage site mutant in vivo analysis, hepcidin mRNA and phospho-Smad readouts The Journal of biological chemistry High 27072365
2021 Hepatocyte-specific Neo1 (neogenin) knockout causes decreased hepcidin expression and iron overload; Neo1 mutant that cannot interact with Hjv (L1046E) fails to correct decreased hepcidin in Neo1 knockout mice; HjvA183R mutant with reduced Neo1 interaction shows blunted hepcidin induction in Hjv-/- mice; Hjv binding triggers cleavage of the Neo1 cytoplasmic domain, leading to accumulation of truncated Neo1 on the plasma membrane where it acts as a scaffold for BMP signaling. Hepatocyte-specific Neo1 conditional knockout mice, Neo1 and Hjv interaction-disrupting mutant reconstitution in vivo, co-immunoprecipitation, protease cleavage analysis of Neo1 cytoplasmic domain Blood High 33824974
2019 HJV in skeletal muscle acts as a coreceptor for TGF-β receptor II (TβRII) rather than activating BMP/Smad1/5/8 (as it does in liver); loss of Hjv in muscle promotes TGF-β1/Smad3 signaling and muscle atrophy; HJV overexpression inhibits TGF-β1/Smad3 signaling by directly interacting with TβRII; overexpression of Hjv rescues dystrophic (mdx) and age-related muscle wasting. Conventional and conditional Hjv knockout mice, Hjv overexpression in mdx and aged mice, co-immunoprecipitation of HJV with TβRII, phospho-Smad2/3 readouts, dual-luciferase reporter assays, treadmill running and isometric force measurements Journal of cachexia, sarcopenia and muscle Medium 30884219
2006 Hemojuvelin (HJV) and transferrin receptor 2 (TfR2) are both localized to the basolateral membrane domain of hepatocytes in rat and human liver, suggesting a possible functional interaction at this membrane domain for iron homeostasis. Immunofluorescence, RT-PCR, immunoblot of rat and human liver and primary human hepatocytes with antibodies against HJV and TfR2 Histochemistry and cell biology Medium 16932966
2015 TMPRSS6 cleaves HJV at residues 121 and 326 (identified by mutagenesis of arginine residues); HJV R121 is critical for rearrangement of the N-terminal heterodimeric HJV; in silico structural modeling indicates some arginines in the von Willebrand domain are inaccessible to TMPRSS6 cleavage due to protein structure. Site-directed mutagenesis of HJV arginine residues to alanine, cleavage assay with TMPRSS6, N-terminal FLAG-tagged HJV fragment analysis, molecular dynamics simulation based on RGMb crystal structure Journal of cellular and molecular medicine Medium 25704252
2008 Neogenin-mediated HJV shedding occurs after HJV traffics to the plasma membrane; HJV endocytosis at the plasma membrane is dynamin-independent and cholesterol-dependent; HJV release is coupled to lysosomal degradation of neogenin; soluble neogenin ectodomain added externally inhibits HJV release, confirming shedding does not occur before cell-surface trafficking. Neogenin siRNA knockdown, soluble neogenin ectodomain competition, dynamin inhibitor, cholesterol depletion with filipin, lysosome inhibitor studies in HepG2 cells The Journal of biological chemistry Medium 18445598

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1980 An immunoglobulin heavy chain variable region gene is generated from three segments of DNA: VH, D and JH. Cell 829 6769593
2006 Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nature genetics 818 16604073
1982 Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions. Proceedings of the National Academy of Sciences of the United States of America 760 6287467
2008 The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell metabolism 438 18976966
1993 Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. International immunology 339 8347558
2005 Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. The Journal of clinical investigation 302 16075058
2007 Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 218 17540841
2005 Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 218 15998830
1990 Biased expression of JH-proximal VH genes occurs in the newly generated repertoire of neonatal and adult mice. The Journal of experimental medicine 206 2261012
2008 Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 184 18326817
2012 The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. Journal of hepatology 146 22728873
2004 Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 139 14982873
2009 Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. Journal of molecular medicine (Berlin, Germany) 137 19229506
2005 Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. The Journal of biological chemistry 114 16103117
2010 Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis. Blood 110 20065295
2004 Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood 106 14982867
2007 Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. The Journal of biological chemistry 98 17331953
2007 Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. American journal of human genetics 98 17847004
2009 Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica 97 19454495
2008 Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness. Blood 90 18997172
2004 The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Human molecular genetics 86 15254010
2014 Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Frontiers in pharmacology 84 24860505
2007 Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site. Blood cells, molecules & diseases 83 17869549
1984 Site-specific recombination between immunoglobulin D and JH segments that were introduced into the genome of a murine pre-B cell line. Cell 72 6327046
2010 The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo. The Journal of biological chemistry 71 20363739
2007 Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. Blood 71 17264300
2009 Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression. The Journal of biological chemistry 65 19564337
2006 Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera. British journal of haematology 63 16939499
2018 Involvement of Met and Kr-h1 in JH-Mediated Reproduction of Female Bactrocera dorsalis (Hendel). Frontiers in physiology 58 29780329
2015 Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin. Hepatology (Baltimore, Md.) 58 26406355
2018 Hepcidin-mediated hypoferremic response to acute inflammation requires a threshold of Bmp6/Hjv/Smad signaling. Blood 57 30213871
2006 Complex biosynthesis of the muscle-enriched iron regulator RGMc. Journal of cell science 56 16868025
2004 Expression of Rgmc, the murine ortholog of hemojuvelin gene, is modulated by development and inflammation, but not by iron status or erythropoietin. Blood 56 15315977
2012 Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage. The Journal of biological chemistry 55 22893705
2010 Matriptase-2- and proprotein convertase-cleaved forms of hemojuvelin have different roles in the down-regulation of hepcidin expression. The Journal of biological chemistry 55 20937842
2016 Internal Duplications of DH, JH, and C Region Genes Create an Unusual IgH Gene Locus in Cattle. Journal of immunology (Baltimore, Md. : 1950) 54 27053761
2011 Structural mechanism of JH delivery in hemolymph by JHBP of silkworm, Bombyx mori. Scientific reports 54 22355650
2014 Comparison of JH signaling in insects and crustaceans. Current opinion in insect science 53 32846733
2009 Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6. British journal of haematology 52 19751239
2011 Conditional disruption of mouse HFE2 gene: maintenance of systemic iron homeostasis requires hepatic but not skeletal muscle hemojuvelin. Hepatology (Baltimore, Md.) 51 21748766
2011 Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis. Blood 50 21493799
2008 RNA interference with the allatoregulating neuropeptide genes from the fall armyworm Spodoptera frugiperda and its effects on the JH titer in the hemolymph. Journal of insect physiology 48 18541256
1994 Neonatal VH, D, and JH gene usage in rabbit B lineage cells. Journal of immunology (Baltimore, Md. : 1950) 47 8283042
2004 Identification and characterization of a juvenile hormone (JH) response region in the JH esterase gene from the spruce budworm, Choristoneura fumiferana. The Journal of biological chemistry 46 14990570
2004 Identification of new mutations of hepcidin and hemojuvelin in patients with HFE C282Y allele. Blood cells, molecules & diseases 45 15528154
2008 Neogenin interacts with hemojuvelin through its two membrane-proximal fibronectin type III domains. Biochemistry 43 18335997
2005 HJV gene mutations in European patients with juvenile hemochromatosis. Clinical genetics 43 15811010
2020 REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks. Proceedings of the National Academy of Sciences of the United States of America 42 33168727
2008 Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin. American journal of physiology. Cell physiology 42 18287331
2014 A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv⁻/⁻ mice. American journal of physiology. Gastrointestinal and liver physiology 40 25501544
1989 Ig VH, DH, and JH germ-line gene segments linked by overlapping cosmid clones of rabbit DNA. Journal of immunology (Baltimore, Md. : 1950) 40 2492580
2017 Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge. Blood 39 29021231
2004 Hepatic and extrahepatic expression of the new iron regulatory protein hemojuvelin. Haematologica 38 15590393
2004 Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis. British journal of haematology 37 15461631
1985 Immunoglobulin JH, C mu, and C gamma gene rearrangements in human B lymphocytes clonally transformed by Epstein-Barr virus. Proceedings of the National Academy of Sciences of the United States of America 37 2982163
2010 The juvenile hormone (JH) epoxide hydrolase gene in the honey bee (Apis mellifera) genome encodes a protein which has negligible participation in JH degradation. Journal of insect physiology 35 20230830
2011 Hemojuvelin: a new link between obesity and iron homeostasis. Obesity (Silver Spring, Md.) 34 21311510
2016 Neogenin Facilitates the Induction of Hepcidin Expression by Hemojuvelin in the Liver. The Journal of biological chemistry 32 27072365
2015 High juvenile hormone titre and abdominal activation of JH signalling may induce reproduction of termite neotenics. Insect molecular biology 32 25847681
2008 Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells. Blood 31 19029439
2006 Expression studies of neogenin and its ligand hemojuvelin in mouse tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 31 16982849
2012 Hepcidin is correlated to soluble hemojuvelin but not to increased GDF15 during pregnancy. Blood cells, molecules & diseases 30 22365732
2008 Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin. BMC biochemistry 30 18384687
2008 Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane. The Journal of biological chemistry 30 18445598
2015 Anti-repulsive Guidance Molecule C (RGMc) Antibodies Increases Serum Iron in Rats and Cynomolgus Monkeys by Hepcidin Downregulation. The AAPS journal 29 25896304
2014 Iron-dependent regulation of hepcidin in Hjv-/- mice: evidence that hemojuvelin is dispensable for sensing body iron levels. PloS one 29 24409331
2012 Iron-mediated retinal degeneration in haemojuvelin-knockout mice. The Biochemical journal 29 21943374
2011 Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma. Laboratory investigation; a journal of technical methods and pathology 29 21863061
2020 Photoperiod and temperature separately regulate nymphal development through JH and insulin/TOR signaling pathways in an insect. Proceedings of the National Academy of Sciences of the United States of America 28 32098850
2018 Deficiency of Brummer Impaires Lipid Mobilization and JH-Mediated Vitellogenesis in the Brown Planthopper, Nilaparvata lugens. Frontiers in physiology 28 30425657
2015 Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin. Journal of molecular medicine (Berlin, Germany) 28 25609138
2015 RXR/USP and EcR are critical for the regulation of reproduction and the control of JH biosynthesis in Diploptera punctata. Journal of insect physiology 28 25917982
2020 Crosstalk among Indoleamines, Neuropeptides and JH/20E in Regulation of Reproduction in the American Cockroach, Periplaneta americana. Insects 26 32121505
2015 The Relationship of Serum Hemojuvelin and Hepcidin Levels with Iron Overload in Nonalcoholic Fatty Liver Disease. Journal of gastrointestinal and liver diseases : JGLD 26 26405701
2010 Immunoassay for human serum hemojuvelin. Haematologica 26 20713458
2009 Hemojuvelin: the hepcidin story continues. Kidney & blood pressure research 26 19287179
2008 Overexpression of Drosophila juvenile hormone esterase binding protein results in anti-JH effects and reduced pheromone abundance. General and comparative endocrinology 26 18275960
1981 Expression of an antigen receptor on T cells does not require recombination at the immunoglobulin JH-C mu locus. Proceedings of the National Academy of Sciences of the United States of America 26 6791163
2015 Effects of juvenile hormone (JH) analog insecticides on larval development and JH esterase activity in two spodopterans. Pesticide biochemistry and physiology 25 26969437
2008 Hemojuvelin N-terminal mutants reach the plasma membrane but do not activate the hepcidin response. Haematologica 25 18827264
2018 Non-HFE mutations in haemochromatosis in China: combination of heterozygous mutations involving HJV signal peptide variants. Journal of medical genetics 24 30166352
2013 Hemojuvelin modulates iron stress during acute kidney injury: improved by furin inhibitor. Antioxidants & redox signaling 24 23901875
2011 Liver hemojuvelin protein levels in mice deficient in matriptase-2 (Tmprss6). Blood cells, molecules & diseases 24 21612955
2000 The interactions between juvenile hormone (JH), lipophorin, vitellogenin, and JH esterases in two cockroach species. Insect biochemistry and molecular biology 24 10876123
2007 Molecular evolution of hemojuvelin and the repulsive guidance molecule family. Journal of molecular evolution 23 17593421
2019 Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review. Orphanet journal of rare diseases 22 31286966
2022 Impact of JH Signaling on Reproductive Physiology of the Classical Insect Model, Rhodnius prolixus. International journal of molecular sciences 21 36430311
2015 Identification of TMPRSS6 cleavage sites of hemojuvelin. Journal of cellular and molecular medicine 21 25704252
2009 Expression of the iron-regulatory protein haemojuvelin in retina and its regulation during cytomegalovirus infection. The Biochemical journal 21 19191760
2023 FDH/Hases-S-chain mediated electron redistributing in Citrobacter freundii JH@FeS during degradation of sulfamethoxazole and nitrate. Water research 20 37572458
2012 Serum hemojuvelin and hepcidin levels in chronic kidney disease. American journal of nephrology 20 22398782
2021 Hepatocyte neogenin is required for hemojuvelin-mediated hepcidin expression and iron homeostasis in mice. Blood 19 33824974
2019 Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age-related muscle wasting. Journal of cachexia, sarcopenia and muscle 19 30884219
2019 Antimicrobial Peptide JH-3 Effectively Kills Salmonella enterica Serovar Typhimurium Strain CVCC541 and Reduces Its Pathogenicity in Mice. Probiotics and antimicrobial proteins 19 31001786
2015 HJV and HFE Play Distinct Roles in Regulating Hepcidin. Antioxidants & redox signaling 19 25608116
2014 Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis. Investigative ophthalmology & visual science 18 24812553
2011 Wnt signaling cross-talks with JH signaling by suppressing Met and gce expression. PloS one 18 22087234
2012 Effect of iron overload and iron deficiency on liver hemojuvelin protein. PloS one 17 22629388
2007 Effect of phlebotomy on hepcidin expression in hemojuvelin-mutant mice. Blood cells, molecules & diseases 17 17395503
2006 Localization of the iron-regulatory proteins hemojuvelin and transferrin receptor 2 to the basolateral membrane domain of hepatocytes. Histochemistry and cell biology 17 16932966

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