Affinage

HJV

Hemojuvelin · UniProt Q6ZVN8

Length
426 aa
Mass
45.1 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HJV (hemojuvelin) is a GPI-anchored BMP coreceptor that serves as the central upstream regulator of hepcidin transcription in hepatocytes, thereby governing systemic iron homeostasis. Membrane-bound HJV enhances signaling by BMP-2, BMP-4, and BMP-6 through type I and type II BMP receptors (including ActRIIA and BMPRII), activating the SMAD1/5/8 cascade that drives hepcidin promoter activity via two BMP-responsive elements; this function requires neogenin, which scaffolds the HJV·BMP·BMP receptor complex at the plasma membrane and undergoes cytoplasmic domain cleavage upon HJV binding (PMID:16604073, PMID:18326817, PMID:19229506, PMID:33824974). HJV is negatively regulated by the serine protease matriptase-2 (TMPRSS6), which cleaves it at Arg121 and Arg326 to release inactive soluble fragments, and by furin/proprotein convertases, which generate a distinct soluble form that acts as a decoy to suppress hepcidin; HFE and TfR2 form a multi-protein complex with HJV that converges on the same SMAD signaling pathway (PMID:18976966, PMID:25704252, PMID:18384687, PMID:22728873, PMID:25609138). Loss-of-function mutations in HJV cause juvenile hemochromatosis (type 2A) characterized by severe iron overload and near-absent hepcidin expression; in skeletal muscle, HJV additionally functions as a TGF-β receptor II coreceptor that suppresses TGF-β1/Smad3 signaling independently of its hepatic BMP coreceptor role (PMID:16075058, PMID:17264300, PMID:21748766, PMID:30884219).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2005 High

    Establishing HJV as an essential positive regulator of hepcidin: HJV-mutant mice developed severe iron overload with dramatically reduced hepcidin, and membrane HJV positively regulated hepcidin mRNA in hepatocytes while soluble HJV acted as a suppressor, defining the opposing roles of membrane versus soluble forms.

    Evidence Hjv-mutant mouse model with hepcidin/iron analysis; siRNA knockdown and recombinant soluble HJV treatment of primary hepatocytes; GPI-anchor characterization and neogenin co-IP in HEK293 cells

    PMID:15998830 PMID:16075058 PMID:16103117

    Open questions at the time
    • Signaling pathway downstream of HJV not yet identified
    • Mechanism of soluble HJV generation unknown
    • How iron modulates HJV shedding unclear
  2. 2006 High

    Identification of HJV as a BMP coreceptor resolved the signaling pathway: HJV enhanced BMP signaling to upregulate hepcidin, and hemochromatosis-associated HJV mutants were defective in BMP signaling, linking disease mechanism to impaired BMP co-receptor function.

    Evidence Cell-based BMP signaling assays, Hfe2-/- hepatocyte studies, reporter assays with disease mutants

    PMID:16604073

    Open questions at the time
    • Specific BMP ligands utilized by HJV not defined
    • Role of BMP type II receptors not characterized
    • Downstream promoter elements mediating BMP/HJV signal unknown
  3. 2006 High

    Biochemical dissection of HJV biosynthesis revealed that HJV undergoes autocatalytic cleavage to generate a disulfide-linked heterodimer at the membrane, and the G320V disease mutant fails this processing step, providing a molecular explanation for loss of function.

    Evidence Pulse-chase, cell-surface labeling, and glycosylation analysis in skeletal muscle cells with disease mutant comparison

    PMID:16868025

    Open questions at the time
    • Protease responsible for autocatalytic cleavage not identified
    • Whether processing is required for BMP co-receptor activity not tested
  4. 2007 High

    Neogenin was established as a regulator of HJV membrane dynamics: iron status controlled HJV shedding via neogenin, and iron stimulated hepcidin through a HJV/BMP2/4-dependent pathway in hepatocytes, while disease-causing HJV mutants showed defective plasma membrane targeting.

    Evidence Iron-deficient rat serum analysis; neogenin siRNA/overexpression in cell lines; holotransferrin treatment of primary hepatocytes; cell-surface labeling of HJV mutants

    PMID:17264300 PMID:17331953 PMID:17540841

    Open questions at the time
    • Molecular mechanism by which neogenin mediates HJV shedding unknown
    • Whether neogenin is required for BMP signaling or only for trafficking unclear
  5. 2008 High

    Multiple studies defined the ligand and receptor specificity of HJV-mediated BMP signaling and its regulation by proteolytic processing: HJV selectively used BMP-2/4/6 with ActRIIA and BMPRII; neogenin bound HJV simultaneously with BMP-2; furin cleaved HJV at a conserved site to generate soluble forms; and HJV trafficking involved an unconventional retrograde pathway from plasma membrane to Golgi.

    Evidence In vitro BMP signaling with receptor combinations; recombinant protein binding/domain mapping; furin cleavage assays with mutagenesis; glycan analysis with endocytosis inhibitors

    PMID:18326817 PMID:18335997 PMID:18384687 PMID:19029439

    Open questions at the time
    • Relative contributions of furin versus other proteases in vivo unclear
    • Structural basis of HJV-BMP interaction not resolved
    • Whether retrograde trafficking is functionally required for signaling not demonstrated
  6. 2008 High

    Matriptase-2 (TMPRSS6) was identified as the physiological protease that cleaves membrane HJV, providing the molecular basis for TMPRSS6 as a negative regulator of hepcidin—HJV cleavage by TMPRSS6 required its serine protease domain and was validated in zebrafish.

    Evidence Cell-based cleavage assays with domain deletion mutants, co-immunoprecipitation, zebrafish functional studies

    PMID:18976966

    Open questions at the time
    • Exact cleavage sites not mapped
    • Whether TMPRSS6 cleavage product differs functionally from furin-generated soluble HJV unknown
  7. 2009 High

    The transcriptional output of HJV/BMP signaling was mapped to two BMP-responsive elements in the hepcidin promoter, and genetic epistasis confirmed HJV as the major in vivo substrate for matriptase-2.

    Evidence Hepcidin promoter-reporter mutagenesis with BMP/IL-6 stimulation; double knockout (TMPRSS6 × Hjv) mouse phenotyping

    PMID:19229506 PMID:19751239

    Open questions at the time
    • Transcription factors binding BMP-REs not identified
    • Whether additional hepcidin regulatory elements exist unknown
  8. 2009 High

    The HJV-neogenin interaction was shown to be functionally required for BMP4-induced hepcidin expression both in vitro and in vivo, establishing neogenin as an obligate partner rather than merely a trafficking factor.

    Evidence Neogenin siRNA in HJV-expressing HepG2 cells; in vivo injection of soluble neogenin fragment in mice

    PMID:19564337

    Open questions at the time
    • Molecular mechanism by which neogenin promotes BMP signaling not defined
    • Whether neogenin interacts directly with BMP receptors untested
  9. 2010 High

    Neogenin-mutant mice confirmed the in vivo requirement for neogenin in HJV-dependent hepcidin regulation, and matriptase-2 cleavage of HJV was mapped to Arg288, producing a soluble form with reduced BMP6 binding distinct from furin-generated soluble HJV.

    Evidence Neogenin-mutant mouse model with hepatocyte BMP/Smad analysis; in vitro cleavage site mapping with BMP6 binding and hepcidin reporter assays

    PMID:20065295 PMID:20937842

    Open questions at the time
    • Additional TMPRSS6 cleavage sites not fully characterized
    • How neogenin stabilizes HJV at the membrane mechanistically unclear
  10. 2011 High

    Tissue-specific knockouts definitively showed that hepatic HJV, not muscle HJV, is necessary and sufficient for hepcidin regulation and systemic iron homeostasis, resolving debate about the tissue source of functional HJV.

    Evidence Hepatocyte-specific and muscle-specific conditional Hjv knockout mice with iron parameter and hepcidin analysis

    PMID:21493799 PMID:21748766

    Open questions at the time
    • Function of muscle HJV unknown at this point
    • Whether HJV has roles in other tissues not tested
  11. 2012 High

    The iron-sensing complex was expanded: HFE, TfR2, and HJV form a multi-protein membrane complex, and neogenin was shown to scaffold a ternary complex with matriptase-2 and HJV that facilitates HJV cleavage at the cell surface.

    Evidence Glycerol gradient sedimentation and co-IP in HuH7 cells for HFE/TfR2/HJV; co-IP and siRNA for neogenin/MT2/HJV ternary complex

    PMID:22728873 PMID:22893705

    Open questions at the time
    • Stoichiometry of the multi-protein complex unknown
    • How iron status remodels complex composition not defined
    • Structural basis of HFE-TfR2-HJV interactions unresolved
  12. 2015 High

    Genetic epistasis established that HFE operates in the same pathway as HJV, TMPRSS6 cleavage sites on HJV were comprehensively mapped to Arg121 and Arg326, and a distinct muscle function for HJV was discovered—acting as a TGF-β receptor II coreceptor to suppress TGF-β1/Smad3 signaling independently of BMP signaling.

    Evidence Double Hfe/Hjv knockout mice; systematic Arg-to-Ala mutagenesis with cleavage assays; co-IP of HJV with TβRII, conditional Hjv knockout and overexpression in muscle/mdx mice

    PMID:25609138 PMID:25704252 PMID:30884219

    Open questions at the time
    • Whether muscle HJV-TGF-β interaction is relevant to other tissues unknown
    • Structural determinants of HJV selectivity for BMP versus TGF-β receptors unresolved
  13. 2016 High

    Neogenin was shown to co-immunoprecipitate with the type I BMP receptor ALK3, and a HJV mutant specifically defective in neogenin binding failed to activate hepcidin in vivo, establishing that neogenin scaffolds the HJV·BMP·BMP receptor signaling complex rather than merely stabilizing HJV.

    Evidence Co-IP of neogenin with ALK3; neogenin-interaction-deficient HJV mutant expressed in Hjv-/- mice; furin cleavage-site mutant showing normal hepcidin in vivo

    PMID:27072365

    Open questions at the time
    • Direct structural evidence for the ternary scaffolding complex lacking
    • Whether neogenin enhances BMP receptor kinase activity or proximity not tested
  14. 2017 High

    Double knockout of Bmp6 and Hjv revealed that BMP6 retains residual signaling capacity without HJV, demonstrating that HJV amplifies rather than absolutely gates BMP6-to-hepcidin signaling, and that full hepcidin induction requires synergy between BMP/SMAD and IL-6/STAT3 pathways.

    Evidence Hjv-/- × Bmp6-/- double knockout mice with Smad signaling and LPS challenge

    PMID:29021231

    Open questions at the time
    • Whether other BMP ligands compensate partially in double knockouts unknown
    • Quantitative contribution of each pathway branch not modeled
  15. 2018 High

    HJV was found to be required for inflammatory hepcidin induction, overturning earlier models that placed inflammatory and iron-sensing pathways as independent—Hjv deficiency abolished the synergism between BMP/Smad and IL-6/Stat signaling needed for the hypoferremic response to infection.

    Evidence Hjv-/- mice challenged with LPS, FSL1, and live E. coli; primary hepatocyte BMP/Smad assays

    PMID:30213871

    Open questions at the time
    • Whether pharmacological BMP supplementation can rescue inflammatory hepcidin in Hjv-/- mice untested
    • Mechanism of synergy between SMAD and STAT3 at the hepcidin promoter not fully resolved
  16. 2021 High

    The molecular mechanism of neogenin scaffolding was elucidated: HJV binding triggers cleavage of the neogenin cytoplasmic domain, and the resulting truncated neogenin accumulates at the plasma membrane where it assembles the BMP signaling complex; interaction-deficient mutants of both neogenin and HJV failed to rescue hepcidin in conditional knockouts.

    Evidence Hepatocyte-specific Neo1 knockout mice; Neo1L1046E and HjvA183R interaction-deficient mutant rescue experiments; BMP signaling analysis

    PMID:33824974

    Open questions at the time
    • Identity of protease cleaving neogenin cytoplasmic domain unknown
    • How truncated neogenin specifically promotes BMP receptor assembly not structurally defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of the HJV·neogenin·BMP·BMP receptor signaling complex, the identity of the protease that cleaves neogenin upon HJV engagement, the mechanism by which iron status is transduced to regulate HJV membrane levels, and whether the muscle TGF-β coreceptor function of HJV has therapeutic relevance for sarcopenia or muscular dystrophy.
  • No high-resolution structure of the HJV signaling complex
  • Iron-sensing mechanism upstream of HJV membrane dynamics unresolved
  • Therapeutic exploitation of muscle HJV-TGF-β axis unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3
Partners
ACVR2AALK3BMPR2HFENEO1TFR2TGFBR2TMPRSS6
Complex memberships
HFE·TfR2·HJV complexHJV·neogenin·BMP·BMP receptor complexNeogenin·matriptase-2·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, and BMP-mediated hepcidin upregulation is blunted in Hfe2-/- hepatocytes. Cell-based BMP signaling assays, Hfe2-/- mouse hepatocytes, reporter assays, co-receptor functional studies Nature genetics High 16604073
2008 The serine protease matriptase-2 (TMPRSS6) cleaves membrane hemojuvelin (HJV) on the plasma membrane, releasing an inactive soluble form and thereby inhibiting hepcidin activation; matriptase-2 lacking the serine protease domain shows no cleavage activity, and matriptase-2 interacts with HJV through its ectodomain. Cell-based cleavage assays, domain deletion mutants, co-immunoprecipitation, zebrafish functional studies Cell metabolism High 18976966
2005 Cell-associated (membrane) HJV positively regulates hepcidin mRNA expression independently of the IL-6 pathway, while recombinant soluble HJV suppresses hepcidin mRNA in primary human hepatocytes in a dose-dependent manner; soluble HJV release from cells is inhibited by increasing iron concentrations. siRNA knockdown of HJV, recombinant soluble HJV treatment of primary hepatocytes, iron-modulation experiments Blood High 15998830
2005 HJV is required for dietary iron sensing in the liver; Hjv-mutant mice exhibit severe iron overload and dramatically decreased hepcidin expression, while cytokine-induced inflammation regulates hepcidin through an Hjv-independent pathway. Hjv-mutant mouse model, hepcidin expression analysis, dietary iron sensing experiments The Journal of clinical investigation High 16075058
2005 HJV is a GPI-anchored protein that undergoes partial autocatalytic cleavage during intracellular processing and co-immunoprecipitates with neogenin but not with the closely related receptor DCC; the G320V hemochromatosis mutant does not co-immunoprecipitate with neogenin; HJV-induced iron accumulation in HEK293 cells requires neogenin. Stable transfection of HJV in HEK293 cells, co-immunoprecipitation, GPI-anchor characterization, iron accumulation assays (transferrin-55Fe) The Journal of biological chemistry High 16103117
2008 HJV selectively uses BMP-2, BMP-4, and BMP-6 as endogenous ligands in hepatoma-derived cells; HJV uses BMP type II receptors ActRIIA and BMPRII but not ActRIIB, and enhances ActRIIA utilization by BMP-2/4; HJV-induced BMP signaling and hepcidin expression are independent of neogenin overexpression or knockdown. In vitro BMP signaling assays, receptor expression studies, neogenin overexpression/siRNA knockdown Blood High 18326817
2012 HFE, TfR2, and HJV form a multi-protein membrane complex on hepatocyte surfaces; HFE and TfR2 bind HJV non-competitively; HJV competes with TfR1 for binding to HFE; residues 120–139 of the TfR2 extracellular domain are required for binding both HFE and HJV. Glycerol gradient sedimentation, co-immunoprecipitation in transfected HuH7 cells, domain mapping Journal of hepatology High 22728873
2007 In iron-deficient rats, HJV shedding into serum increases without changes in HFE2 mRNA or protein levels; holo-transferrin suppresses HJV shedding in C2C12 and HepG2 cells; neogenin knockdown suppresses HJV shedding while neogenin overexpression enhances it, indicating HJV membrane shedding is mediated by neogenin. Iron-deficient rat model, holo-transferrin treatment, siRNA knockdown and overexpression of neogenin, cell-based shedding assays The Journal of biological chemistry High 17331953
2010 Neogenin inhibits HJV secretion and stabilizes membrane HJV; livers of neogenin-mutant mice exhibit iron overload, low hepcidin, and reduced BMP signaling; mutant hepatocytes show impaired BMP2-induced Smad1/5/8 phosphorylation and hepcidin expression. Neogenin mutant mouse model, hepatocyte culture BMP signaling assays, Smad phosphorylation analysis Blood High 20065295
2007 Iron stimulates hepcidin expression in primary murine hepatocytes through a hemojuvelin/BMP2/4-dependent pathway; BMP9, although expressed in liver, does not interact with hemojuvelin and its pathway does not affect iron regulation of hepcidin. Primary murine hepatocyte culture with holotransferrin, BMP neutralization experiments, siRNA knockdown of hemojuvelin Blood High 17540841
2009 The HJV-neogenin interaction is required for BMP4-induced hepcidin expression; knockdown of neogenin in HJV-expressing HepG2 cells decreases BMP4-induced hepcidin mRNA 16-fold; disruption of the HJV-neogenin interaction markedly suppresses hepcidin; in vivo blocking of HJV-neogenin interaction with soluble neogenin fragment suppresses hepatic hepcidin in mice. siRNA knockdown of neogenin in HJV-expressing HepG2 cells, in vivo injection of soluble neogenin fragment in mice, G99V mutant analysis The Journal of biological chemistry High 19564337
2012 Neogenin interacts with matriptase-2 (MT2) as well as with HJV, forming a ternary complex at the plasma membrane that facilitates MT2 cleavage of HJV; neogenin knockdown with siRNA increases MT2 and HJV on the plasma membrane; MT2 cleavage of cell-surface HJV is coupled to a transition from high-mannose to complex oligosaccharides on HJV. Co-immunoprecipitation, siRNA knockdown, oligosaccharide analysis, cell-surface cleavage assays The Journal of biological chemistry High 22893705
2010 Matriptase-2 cleaves HJV at Arg288, producing a soluble HJV form with decreased ability to bind BMP6 that does not suppress BMP6-induced hepcidin expression, distinct from the proprotein convertase (furin) cleavage product which does suppress hepcidin. In vitro cleavage assay, BMP6 binding assay, hepcidin reporter assay The Journal of biological chemistry High 20937842
2008 HJV undergoes autocatalytic cleavage generating a disulfide-linked heterodimer; neogenin binds to both cleaved and uncleaved HJV; the HJV-neogenin binding site maps to the membrane-proximal fifth and sixth FNIII domains of neogenin; BMP-2 and neogenin can bind HJV simultaneously, raising the possibility of a multiprotein complex. Recombinant protein production, binding assays, domain mapping with neogenin fragments, BMP-2 competition assays Biochemistry High 18335997
2006 HJV (RGMc) undergoes complex biosynthesis in skeletal muscle: two GPI-anchored glycosylated forms are produced — a full-length species released into extracellular fluid and a disulfide-linked heterodimer of N- and C-terminal fragments at the membrane; the G320V disease mutant fails to generate the heterodimeric membrane isoform. Pulse-chase studies, cell-surface labeling, glycosylation analysis, disease mutant characterization Journal of cell science High 16868025
2007 Defective plasma membrane targeting of HJV is a common pathogenetic mechanism in juvenile hemochromatosis; proteolytic processing (autocleavage) is required for membrane export; mutants F170S, W191C, and G320V are retained in the ER and fail to reach the cell surface; membrane HJV level is increased by iron in wild-type but not mutant mice. HeLa and HepG2 cell transfection, cell-surface labeling, immunoblot analysis of processing, iron supplementation experiments Blood High 17264300
2008 HJV processing requires retrograde trafficking from the plasma membrane back to the Golgi; cellular HJV reaches the plasma membrane with high-mannose oligosaccharides (bypassing Golgi processing), while secreted HJV has complex oligosaccharides derived from plasma membrane HJV after retrograde trafficking; neogenin is required for HJV release/shedding but not for trafficking to the cell surface. Glycosylation analysis, neogenin knockdown, endocytosis inhibitors (dynamin-independent, cholesterol-dependent pathway), HepG2 cells Blood High 19029439
2008 Pro-protein convertases (PCs), including furin, cleave 50 kDa RGMc/HJV at a conserved PC recognition site to generate a 40 kDa species with truncated C-terminus; cell-impermeable PC inhibitor blocks extracellular 40 kDa HJV; iron loading reduces HJV release from the cell membrane and diminishes accumulation of the 40 kDa species. Furin in vitro cleavage assay, PC inhibitor experiments, site-directed mutagenesis of cleavage site, iron-loading cell culture BMC biochemistry High 18384687
2008 Neogenin-mediated HJV shedding occurs after HJV traffics to the plasma membrane; neogenin knockdown suppresses HJV release without affecting plasma membrane trafficking; HJV endocytosis is dynamin-independent and cholesterol-dependent; HJV release is coupled to lysosomal degradation of neogenin. Neogenin knockdown, cholesterol depletion (filipin), lysosomal inhibitor experiments, HepG2 cells The Journal of biological chemistry High 18445598
2009 Two BMP-responsive elements (BMP-RE1 at -84/-79 and BMP-RE2 at -2255/-2250) in the hepcidin promoter are both critical for basal hepcidin expression and response to BMP-2, BMP-6, and HJV-mediated BMP signals; BMP-RE1 is specifically required for IL-6 response while both elements show additive effects for HJV/BMP signals. Hepcidin promoter reporter assays, BMP-RE mutagenesis, BMP-2/BMP-6/IL-6 stimulation experiments Journal of molecular medicine High 19229506
2011 Hepatic HJV, but not skeletal muscle HJV, is necessary and sufficient for hepcidin regulation and systemic iron homeostasis; liver-specific Hjv knockout causes iron overload comparable to ubiquitous Hjv-/- mice with marked hepcidin suppression, while muscle-specific Hjv knockout causes no iron phenotype. Tissue-specific conditional Hjv knockout mice (hepatocyte- and muscle-specific Cre), iron parameter analysis, hepcidin mRNA quantification Hepatology High 21493799 21748766
2015 In skeletal muscle, HJV acts as a coreceptor for TGF-β receptor II (TβRII) and inhibits TGF-β1/Smad3 signaling; HJV directly interacts with TβRII on the muscle membrane, and loss of HJV increases TGF-β1, TβRII, and p-Smad2/3 without altering the BMP/p-Smad1/5/8 pathway in muscle; overexpression of Hjv rescues dystrophic and age-related muscle wasting. Co-immunoprecipitation, dual-luciferase reporter assay, RNAi, conditional Hjv knockout mice, mdx mice, Hjv overexpression vector in vivo Journal of cachexia, sarcopenia and muscle High 30884219
2021 Hepatocyte neogenin is required for HJV-mediated hepcidin expression and iron homeostasis; hepatocyte-specific Neo1 knockout mice develop iron overload and reduced hepcidin; the Neo1L1046E mutant that cannot interact with HJV fails to rescue the phenotype; HjvA183R with reduced Neo1 interaction shows blunted hepcidin induction; 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 complex assembly. Hepatocyte-specific Neo1 conditional knockout mice, interaction-deficient mutants (Neo1L1046E, HjvA183R), rescue experiments, BMP signaling analysis Blood High 33824974
2016 Neogenin co-immunoprecipitates with ALK3 (type I BMP receptor); a HJV mutation specifically reducing neogenin interaction dramatically attenuates BMP signaling and hepcidin mRNA when expressed in Hjv-/- mice; furin-cleavage site mutation in Hjv does not alter hepcidin stimulation in vivo; neogenin acts as a scaffold facilitating assembly of the HJV·BMP·BMP receptor complex. Co-immunoprecipitation of neogenin with ALK3, neogenin-interaction mutant HJV in Hjv-/- mice, furin cleavage site mutant in vivo The Journal of biological chemistry High 27072365
2018 Hjv is required for inflammatory induction of hepcidin and the acute hypoferremic response to LPS, FSL1, and E. coli infection; Hjv deficiency severely impairs BMP6/Smad signaling and abolishes synergism with the IL-6/Stat pathway; Hfe-/- mice show near-normal inflammatory hepcidin; double Hjv-/-Hfe-/- mice phenocopy Hjv-/- mice. Hjv-/- and Hfe-/- mouse models with LPS/FSL1/E. coli challenge, primary hepatocyte BMP signaling assays, Smad phosphorylation analysis Blood High 30213871
2017 BMP6 and HJV can signal to hepcidin partially independently; loss of Bmp6 further represses Smad signaling and hepcidin in Hjv-/- mice, indicating BMP6 provides a residual signal in the absence of HJV; both BMP6 and HJV are required for full hepcidin induction, with synergy between BMP/SMAD and IL-6/STAT3 pathways. Hjv-/- × Bmp6-/- double knockout mice, Smad signaling analysis, LPS challenge, iron accumulation analysis Blood High 29021231
2015 HFE and HJV operate in the same pathway for hepcidin regulation; combined Hfe-/- Hjv-/- double knockout mice phenocopy single Hjv-/- mice with indistinguishable hepcidin suppression and iron overload, indicating HFE function is epistatic to or converges with HJV for hepcidin and Smad signaling. Double Hfe-/- Hjv-/- knockout mouse generation and phenotypic analysis, Smad signaling, iron parameters Journal of molecular medicine High 25609138
2015 TMPRSS6 cleaves HJV at residues Arg121 and Arg326 in both full-length and heterodimeric HJV isoforms; Arg176 and Arg288 contribute to additional cleavage; molecular dynamics modeling of HJV structure identified TMPRSS6-insensitive arginines within the von Willebrand domain due to partial protein structure destabilization. Arginine-to-alanine mutagenesis, cell-based cleavage assays, N-terminal FLAG-tagged HJV analysis, in silico molecular dynamics simulation Journal of cellular and molecular medicine High 25704252
2008 BMP-2 binds to single-chain RGMc/HJV species in biochemical assays and to cell-associated RGMc; disease mutants D172E and G320V show reduced BMP-2 binding; G99V cannot bind BMP-2; neogenin preferentially binds heterodimeric membrane RGMc and can interact with wild-type RGMc and G99V but not G320V or D172E on cells. Biochemical binding assays, cell-based binding assays, pulldown, disease mutant analysis American journal of physiology. Cell physiology Medium 18287331
2010 HFE-mediated hepcidin induction requires hemojuvelin (Hjv); overexpression of Hfe in the liver does not require the HFE cytoplasmic domain to induce hepcidin but does require Hjv; Hfe transgene-driven hepcidin induction is greatly attenuated in Hjv-/- mice. Transgenic mouse overexpression of Hfe with deleted cytoplasmic domain, Hjv-/- × Hfe transgenic crosses, hepcidin expression analysis Blood High 20837779
2009 Mice lacking both functional matriptase-2 and hemojuvelin exhibit low hepcidin (Hamp1) expression and high serum/liver iron, consistent with hemojuvelin being a major in vivo substrate for matriptase-2; double mutant mice also show lower cardiac iron than single Hjv-/- mice, suggesting cardioprotective effect of matriptase-2 loss. Double knockout (matriptase-2 protease domain × Hjv-/-) mouse generation and phenotypic analysis British journal of haematology High 19751239
2012 In haemojuvelin-knockout (Hjv-/-) mice, iron accumulates in the retina with age, causing morphological damage; HJV-deficient RPE cells have a hyperproliferative phenotype and up-regulated xCT; BMP6 cannot induce hepcidin expression in Hjv-/- RPE cells, confirming that retinal cells require HJV for BMP6-mediated hepcidin pathway activation. Hjv-/- mouse retinal histology, primary RPE cell culture, BMP6 stimulation and hepcidin promoter assays The Biochemical journal Medium 21943374

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1985 Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1060 3924412
2006 Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nature genetics 816 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 756 6287467
1984 Preferential utilization of the most JH-proximal VH gene segments in pre-B-cell lines. Nature 685 6092962
2008 The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell metabolism 437 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
2005 Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 218 15998830
2007 Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 216 17540841
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 144 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) 136 19229506
1989 Autoantibodies encoded by the most Jh-proximal human immunoglobulin heavy chain variable region gene. The Journal of experimental medicine 116 2507728
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 109 20065295
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
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 83 24860505
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
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
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