{"gene":"HJV","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2006,"finding":"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.","method":"BMP signaling assays in transfected cells, Hfe2-/- mouse hepatocyte studies, luciferase reporter assays, phospho-SMAD readouts","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (cell-based BMP signaling assays, mutagenesis of disease-linked mutants, knockout mouse hepatocytes), replicated by multiple subsequent labs","pmids":["16604073"],"is_preprint":false},{"year":2005,"finding":"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.","method":"siRNA knockdown of HJV in hepatocyte cell lines, recombinant soluble HJV treatment of primary human hepatocytes, iron concentration titration experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with hepcidin mRNA readout, recombinant protein treatment of primary cells, iron dose-response; single lab but multiple orthogonal approaches","pmids":["15998830"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Stable transfection of HJV cDNA into HEK293 cells, co-immunoprecipitation, GPI-anchor characterization, transferrin-55Fe accumulation assays, immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional iron accumulation assay, mutant analysis; single lab with multiple orthogonal methods","pmids":["16103117"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Hjv-mutant mouse model, quantitative gene expression analysis, tissue-specific expression by in situ/IHC, LPS-induced inflammation model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout mouse with defined hepcidin phenotype, replicated by multiple labs","pmids":["16075058"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Cleavage assays in transfected cells, domain deletion mutants, interaction mapping by co-immunoprecipitation, zebrafish in vivo model expressing matriptase-2 mutants","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — enzymatic cleavage assay with mutagenesis of active site, Co-IP interaction mapping, in vivo zebrafish validation; multiple orthogonal methods in a single rigorous study","pmids":["18976966"],"is_preprint":false},{"year":2008,"finding":"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.","method":"BMP ligand binding assays, receptor co-transfection/signaling studies in hepatoma cell lines, siRNA knockdown of neogenin, hepcidin reporter assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic receptor/ligand interaction mapping with multiple BMP ligands and receptors, siRNA knockdown, functional hepcidin readout; single lab with multiple orthogonal approaches","pmids":["18326817"],"is_preprint":false},{"year":2007,"finding":"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).","method":"Proprotein convertase inhibitor studies, site-directed mutagenesis of RNRR cleavage site, iron treatment experiments in cell lines","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cleavage site identified by mutagenesis and inhibitor studies; single lab but two orthogonal approaches","pmids":["17869549"],"is_preprint":false},{"year":2007,"finding":"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.","method":"siRNA knockdown of neogenin in C2C12 cells, neogenin overexpression in HEK293 cells, holotransferrin dose-response in cell lines, in vivo iron-deficient rat model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and overexpression experiments, in vivo rat model; single lab with multiple orthogonal approaches","pmids":["17331953"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Primary murine hepatocyte culture, holotransferrin and apotransferrin treatment, hemojuvelin/BMP pathway inhibition, siRNA knockdown","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary hepatocyte system with pathway-specific inhibition; single lab with multiple reagents","pmids":["17540841"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Recombinant protein expression, biochemical binding assays, domain-deletion mapping of neogenin ectodomain, surface plasmon resonance or equivalent binding affinity measurements","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic binding domain mapping with recombinant proteins; single lab with quantitative binding characterization","pmids":["18335997"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Biochemical BMP-2 binding assays, cell-surface interaction studies with neogenin for wild-type and mutant RGMc/HJV","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutant analysis with binding assays; single lab, two orthogonal approaches","pmids":["18287331"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Pulse-chase studies, cell-surface labeling, glycosylation analysis, immunoblot, mutagenesis of disease-associated G320V variant","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulse-chase with cell-surface labeling and mutagenesis; single lab with multiple biochemical approaches","pmids":["16868025"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Expression of HJV pathogenic mutants in HeLa and HepG2 cells, cell-surface localization assays, biosynthesis/processing analysis, in vivo iron treatment of mice","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutants analyzed by cell biology approaches including surface labeling and ER retention assays; single lab with multiple orthogonal methods","pmids":["17264300"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Oligosaccharide analysis (Endo H and PNGase F digestion), neogenin siRNA knockdown, cholesterol depletion with filipin, dynamin inhibition, pulse-chase in HepG2 cells","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — glycan processing analysis plus trafficking inhibitor studies in hepatoma cells; single lab, multiple orthogonal methods","pmids":["19029439"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Site-directed mutagenesis of HJV arginine residues, cleavage assays, BMP6 binding assays, hepcidin expression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — enzymatic cleavage site identification by mutagenesis with functional BMP binding and hepcidin activity readouts; single lab","pmids":["20937842"],"is_preprint":false},{"year":2008,"finding":"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.","method":"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","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro furin cleavage assay plus cell-based inhibitor and mutagenesis studies; single lab with multiple orthogonal methods","pmids":["18384687"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Glycerol gradient sedimentation assays, co-immunoprecipitation in transfected HuH7 hepatoma cells, domain-deletion mapping","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation with sedimentation assay and domain mapping; single lab with two orthogonal methods","pmids":["22728873"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA knockdown of neogenin in HepG2 cells, HJV/neogenin interaction disruption experiments, in vivo mouse injection of soluble neogenin fragment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with hepcidin readout and in vivo validation; single lab with in vitro/in vivo orthogonal approaches","pmids":["19564337"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Neogenin mutant mouse model, in vitro hepatocyte BMP/Smad signaling assays, HJV secretion assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with defined iron phenotype plus mechanistic in vitro assays; single lab","pmids":["20065295"],"is_preprint":false},{"year":2012,"finding":"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.","method":"siRNA knockdown of neogenin, co-immunoprecipitation, N-linked oligosaccharide analysis, cell-surface cleavage assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA, Co-IP, glycan analysis; single lab with multiple orthogonal methods","pmids":["22893705"],"is_preprint":false},{"year":2009,"finding":"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.","method":"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":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter dissection by mutagenesis with multiple stimuli; single lab","pmids":["19229506"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Tissue-specific conditional knockout mice (liver- and muscle-specific), serum/hepatic iron measurements, hepcidin and BMP6 mRNA quantification","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional tissue-specific knockout mice replicated by independent lab (PMID:21493799) with consistent conclusion","pmids":["21748766","21493799"],"is_preprint":false},{"year":2010,"finding":"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.","method":"AAV-mediated hepatocyte-specific HJV reconstitution in Hjv-/- mice, hepcidin mRNA quantification, phospho-Smad1/5/8 immunoblot, BMP6 mRNA quantification under iron depletion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo gene reconstitution with quantitative hepcidin and Smad signaling readouts; rigorous single-lab study with multiple orthogonal measures","pmids":["20363739"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Hjv-/- mouse LPS/infection challenge models, ferroportin immunofluorescence in macrophages, primary hepatocyte BMP2 and BMP6 signaling assays, phospho-Smad readouts","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse models with multiple inflammatory stimuli plus primary hepatocyte mechanistic assays; rigorous multi-method study","pmids":["30213871"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Hjv-/- x Bmp6-/- double knockout mouse generation and phenotypic analysis, Smad5 phosphorylation, serum hepcidin, organ iron measurements","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double knockout mouse genetic epistasis with quantitative molecular readouts; rigorous in vivo study","pmids":["26406355"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Hfe-/- x Hjv-/- double knockout mouse generation, hepcidin mRNA, serum/hepatic iron, Smad signaling analysis under standard and iron-enriched diets","journal":"Journal of molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — double knockout genetic epistasis with comprehensive phenotypic and molecular characterization; replicated by Wu et al. 2015 (PMID:25608116)","pmids":["25609138","25608116"],"is_preprint":false},{"year":2016,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mutagenesis reconstitution plus Co-IP and multiple mechanistic readouts in a single rigorous study","pmids":["27072365"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Hepatocyte-specific Neo1 conditional knockout mice, Neo1 and Hjv interaction-disrupting mutant reconstitution in vivo, co-immunoprecipitation, protease cleavage analysis of Neo1 cytoplasmic domain","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout mouse combined with in vivo mutant reconstitution and biochemical mechanism; rigorous multi-method single study","pmids":["33824974"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, knockout and overexpression mouse models with functional phenotype; single lab with multiple orthogonal methods","pmids":["30884219"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Immunofluorescence, RT-PCR, immunoblot of rat and human liver and primary human hepatocytes with antibodies against HJV and TfR2","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization by immunofluorescence in native tissue; replicated finding of basolateral localization; single lab","pmids":["16932966"],"is_preprint":false},{"year":2015,"finding":"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.","method":"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":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — systematic mutagenesis with enzymatic cleavage assay; single lab with in silico modeling support","pmids":["25704252"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Neogenin siRNA knockdown, soluble neogenin ectodomain competition, dynamin inhibitor, cholesterol depletion with filipin, lysosome inhibitor studies in HepG2 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic inhibition approaches; single lab","pmids":["18445598"],"is_preprint":false}],"current_model":"Hemojuvelin (HJV) is a GPI-anchored membrane protein that functions primarily in hepatocytes as a co-receptor for BMP ligands (BMP-2, BMP-4, BMP-6), assembling with BMP type I receptors (ALK2/ALK3) and type II receptors (ActRIIA/BMPRII) in a complex scaffolded by neogenin to activate SMAD1/5/8 phosphorylation and transcription of the iron hormone hepcidin; soluble HJV, released by proprotein convertase (furin, at the RNRR site) or by the serine protease matriptase-2/TMPRSS6 (at Arg121/Arg326), acts as a decoy receptor that competes with membrane HJV for BMP ligands and suppresses hepcidin; iron loading promotes membrane HJV retention while iron deficiency increases soluble HJV shedding; HFE, TfR2, and HJV form a multi-protein membrane complex for coordinated iron sensing; and in skeletal muscle HJV additionally suppresses TGF-β1/Smad2/3 signaling by directly interacting with TGF-β receptor II, a mechanistically distinct function from its hepatic BMP co-receptor role."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2005,"claim":"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","pmids":["16103117"],"confidence":"High","gaps":["Functional consequence of neogenin binding for hepcidin not yet defined","Did not link HJV to BMP signaling"]},{"year":2005,"claim":"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","pmids":["15998830"],"confidence":"High","gaps":["Protease responsible for shedding unknown","Molecular target of soluble HJV not identified"]},{"year":2005,"claim":"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","pmids":["16075058"],"confidence":"High","gaps":["Molecular signaling pathway not resolved","Cell-autonomous vs systemic contribution untested"]},{"year":2006,"claim":"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","pmids":["16604073"],"confidence":"High","gaps":["Specific BMP ligands and receptors not yet enumerated","Role of neogenin in signaling unclear"]},{"year":2006,"claim":"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","pmids":["16868025","16932966"],"confidence":"Medium","gaps":["Functional role of heterodimer in signaling untested","TfR2 co-localization not yet shown to be a direct interaction"]},{"year":2007,"claim":"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","pmids":["17869549","17331953"],"confidence":"Medium","gaps":["Whether furin product is the physiological decoy in vivo unresolved","Mechanism by which neogenin promotes shedding not defined"]},{"year":2007,"claim":"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","pmids":["17540841"],"confidence":"Medium","gaps":["Direct link between transferrin sensing and HJV not biochemically defined","Single primary-hepatocyte system"]},{"year":2008,"claim":"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","pmids":["18976966"],"confidence":"High","gaps":["Exact cleavage residues not yet mapped","Functional properties of the soluble product not characterized"]},{"year":2008,"claim":"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","pmids":["18326817"],"confidence":"High","gaps":["Stoichiometry of the receptor complex not determined","Apparent dispensability of neogenin here conflicts with later in vivo data"]},{"year":2008,"claim":"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","pmids":["18335997"],"confidence":"Medium","gaps":["In vivo relevance of simultaneous binding not tested here","Affinities of competing interactions not ranked"]},{"year":2008,"claim":"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","pmids":["19029439","17264300","18445598","18384687"],"confidence":"Medium","gaps":["Precise sequence of cleavage and trafficking steps still partly inferred","Single-lab trafficking conclusions"]},{"year":2008,"claim":"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","pmids":["18287331"],"confidence":"Medium","gaps":["Functional hepcidin output of each mutant not measured here","In vivo correlation lacking"]},{"year":2009,"claim":"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","pmids":["19229506","19564337"],"confidence":"Medium","gaps":["Conflict with prior report that neogenin was dispensable for signaling","SMAD occupancy of BMP-REs not directly shown"]},{"year":2010,"claim":"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","pmids":["20065295","20937842"],"confidence":"Medium","gaps":["Exact cleavage residue not unified across studies","Relative in vivo contribution of furin vs matriptase-2 products unresolved"]},{"year":2010,"claim":"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","pmids":["21748766","21493799","20363739"],"confidence":"High","gaps":["Mechanism of muscle HJV not addressed here","BMP6 mRNA regulation found independent of HJV, leaving the sensing input upstream of HJV open"]},{"year":2012,"claim":"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","pmids":["22728873","22893705"],"confidence":"Medium","gaps":["Stoichiometry and dynamics of the complexes unknown","Single-lab biochemistry"]},{"year":2015,"claim":"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","pmids":["25609138","25608116","26406355"],"confidence":"High","gaps":["Molecular basis of HJV-independent BMP6 signaling unresolved","Sex-specific differences not mechanistically explained"]},{"year":2015,"claim":"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","pmids":["25704252"],"confidence":"Medium","gaps":["Reconciliation with earlier Arg288/Arg774C mapping incomplete","In vivo relevance of individual sites untested"]},{"year":2016,"claim":"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","pmids":["27072365"],"confidence":"High","gaps":["How neogenin connects HJV to ALK3 mechanistically not fully resolved here","Decoy function of soluble HJV not addressed in vivo"]},{"year":2019,"claim":"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","pmids":["30884219"],"confidence":"Medium","gaps":["Structural basis of HJV–TβRII interaction unknown","Relationship to HJV's GPI-anchored processing in muscle unclear"]},{"year":2021,"claim":"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","pmids":["33824974"],"confidence":"High","gaps":["Protease cleaving the neogenin cytoplasmic domain not identified","How truncated neogenin scaffold engages ALK3/SMAD not fully detailed"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,28]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,22]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,12,29,19]},{"term_id":"GO:0005794","term_label":"Golgi 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SLC39A14","url":"https://www.omim.org/entry/608736"},{"mim_id":"608374","title":"HEMOJUVELIN BMP CORECEPTOR; HJV","url":"https://www.omim.org/entry/608374"},{"mim_id":"606464","title":"HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP","url":"https://www.omim.org/entry/606464"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":223.7},{"tissue":"skeletal 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mediated electron redistributing in Citrobacter freundii JH@FeS during degradation of sulfamethoxazole and nitrate.","date":"2023","source":"Water research","url":"https://pubmed.ncbi.nlm.nih.gov/37572458","citation_count":20,"is_preprint":false},{"pmid":"25608116","id":"PMC_25608116","title":"HJV and HFE Play Distinct Roles in Regulating Hepcidin.","date":"2015","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25608116","citation_count":19,"is_preprint":false},{"pmid":"33824974","id":"PMC_33824974","title":"Hepatocyte neogenin is required for hemojuvelin-mediated hepcidin expression and iron homeostasis in mice.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/33824974","citation_count":19,"is_preprint":false},{"pmid":"30884219","id":"PMC_30884219","title":"Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age-related muscle wasting.","date":"2019","source":"Journal of cachexia, sarcopenia and 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cells, Hfe2-/- mouse hepatocyte studies, luciferase reporter assays, phospho-SMAD readouts\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (cell-based BMP signaling assays, mutagenesis of disease-linked mutants, knockout mouse hepatocytes), replicated by multiple subsequent labs\",\n      \"pmids\": [\"16604073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of HJV in hepatocyte cell lines, recombinant soluble HJV treatment of primary human hepatocytes, iron concentration titration experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with hepcidin mRNA readout, recombinant protein treatment of primary cells, iron dose-response; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"15998830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Stable transfection of HJV cDNA into HEK293 cells, co-immunoprecipitation, GPI-anchor characterization, transferrin-55Fe accumulation assays, immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional iron accumulation assay, mutant analysis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16103117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Hjv-mutant mouse model, quantitative gene expression analysis, tissue-specific expression by in situ/IHC, LPS-induced inflammation model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout mouse with defined hepcidin phenotype, replicated by multiple labs\",\n      \"pmids\": [\"16075058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Cleavage assays in transfected cells, domain deletion mutants, interaction mapping by co-immunoprecipitation, zebrafish in vivo model expressing matriptase-2 mutants\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — enzymatic cleavage assay with mutagenesis of active site, Co-IP interaction mapping, in vivo zebrafish validation; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"18976966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"BMP ligand binding assays, receptor co-transfection/signaling studies in hepatoma cell lines, siRNA knockdown of neogenin, hepcidin reporter assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic receptor/ligand interaction mapping with multiple BMP ligands and receptors, siRNA knockdown, functional hepcidin readout; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"18326817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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).\",\n      \"method\": \"Proprotein convertase inhibitor studies, site-directed mutagenesis of RNRR cleavage site, iron treatment experiments in cell lines\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cleavage site identified by mutagenesis and inhibitor studies; single lab but two orthogonal approaches\",\n      \"pmids\": [\"17869549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of neogenin in C2C12 cells, neogenin overexpression in HEK293 cells, holotransferrin dose-response in cell lines, in vivo iron-deficient rat model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and overexpression experiments, in vivo rat model; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"17331953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Primary murine hepatocyte culture, holotransferrin and apotransferrin treatment, hemojuvelin/BMP pathway inhibition, siRNA knockdown\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary hepatocyte system with pathway-specific inhibition; single lab with multiple reagents\",\n      \"pmids\": [\"17540841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein expression, biochemical binding assays, domain-deletion mapping of neogenin ectodomain, surface plasmon resonance or equivalent binding affinity measurements\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic binding domain mapping with recombinant proteins; single lab with quantitative binding characterization\",\n      \"pmids\": [\"18335997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical BMP-2 binding assays, cell-surface interaction studies with neogenin for wild-type and mutant RGMc/HJV\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutant analysis with binding assays; single lab, two orthogonal approaches\",\n      \"pmids\": [\"18287331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Pulse-chase studies, cell-surface labeling, glycosylation analysis, immunoblot, mutagenesis of disease-associated G320V variant\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse-chase with cell-surface labeling and mutagenesis; single lab with multiple biochemical approaches\",\n      \"pmids\": [\"16868025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Expression of HJV pathogenic mutants in HeLa and HepG2 cells, cell-surface localization assays, biosynthesis/processing analysis, in vivo iron treatment of mice\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutants analyzed by cell biology approaches including surface labeling and ER retention assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17264300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Oligosaccharide analysis (Endo H and PNGase F digestion), neogenin siRNA knockdown, cholesterol depletion with filipin, dynamin inhibition, pulse-chase in HepG2 cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — glycan processing analysis plus trafficking inhibitor studies in hepatoma cells; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19029439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of HJV arginine residues, cleavage assays, BMP6 binding assays, hepcidin expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — enzymatic cleavage site identification by mutagenesis with functional BMP binding and hepcidin activity readouts; single lab\",\n      \"pmids\": [\"20937842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro furin cleavage assay plus cell-based inhibitor and mutagenesis studies; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18384687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Glycerol gradient sedimentation assays, co-immunoprecipitation in transfected HuH7 hepatoma cells, domain-deletion mapping\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation with sedimentation assay and domain mapping; single lab with two orthogonal methods\",\n      \"pmids\": [\"22728873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of neogenin in HepG2 cells, HJV/neogenin interaction disruption experiments, in vivo mouse injection of soluble neogenin fragment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with hepcidin readout and in vivo validation; single lab with in vitro/in vivo orthogonal approaches\",\n      \"pmids\": [\"19564337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Neogenin mutant mouse model, in vitro hepatocyte BMP/Smad signaling assays, HJV secretion assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with defined iron phenotype plus mechanistic in vitro assays; single lab\",\n      \"pmids\": [\"20065295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of neogenin, co-immunoprecipitation, N-linked oligosaccharide analysis, cell-surface cleavage assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA, Co-IP, glycan analysis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22893705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Hepcidin promoter reporter assays with BMP-RE1 and BMP-RE2 mutations in hepatoma cells, BMP-2/BMP-6 and HJV transfection, IL-6 stimulation\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter dissection by mutagenesis with multiple stimuli; single lab\",\n      \"pmids\": [\"19229506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Tissue-specific conditional knockout mice (liver- and muscle-specific), serum/hepatic iron measurements, hepcidin and BMP6 mRNA quantification\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional tissue-specific knockout mice replicated by independent lab (PMID:21493799) with consistent conclusion\",\n      \"pmids\": [\"21748766\", \"21493799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"AAV-mediated hepatocyte-specific HJV reconstitution in Hjv-/- mice, hepcidin mRNA quantification, phospho-Smad1/5/8 immunoblot, BMP6 mRNA quantification under iron depletion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene reconstitution with quantitative hepcidin and Smad signaling readouts; rigorous single-lab study with multiple orthogonal measures\",\n      \"pmids\": [\"20363739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Hjv-/- mouse LPS/infection challenge models, ferroportin immunofluorescence in macrophages, primary hepatocyte BMP2 and BMP6 signaling assays, phospho-Smad readouts\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse models with multiple inflammatory stimuli plus primary hepatocyte mechanistic assays; rigorous multi-method study\",\n      \"pmids\": [\"30213871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Hjv-/- x Bmp6-/- double knockout mouse generation and phenotypic analysis, Smad5 phosphorylation, serum hepcidin, organ iron measurements\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double knockout mouse genetic epistasis with quantitative molecular readouts; rigorous in vivo study\",\n      \"pmids\": [\"26406355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Hfe-/- x Hjv-/- double knockout mouse generation, hepcidin mRNA, serum/hepatic iron, Smad signaling analysis under standard and iron-enriched diets\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double knockout genetic epistasis with comprehensive phenotypic and molecular characterization; replicated by Wu et al. 2015 (PMID:25608116)\",\n      \"pmids\": [\"25609138\", \"25608116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mutagenesis reconstitution plus Co-IP and multiple mechanistic readouts in a single rigorous study\",\n      \"pmids\": [\"27072365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Hepatocyte-specific Neo1 conditional knockout mice, Neo1 and Hjv interaction-disrupting mutant reconstitution in vivo, co-immunoprecipitation, protease cleavage analysis of Neo1 cytoplasmic domain\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout mouse combined with in vivo mutant reconstitution and biochemical mechanism; rigorous multi-method single study\",\n      \"pmids\": [\"33824974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, knockout and overexpression mouse models with functional phenotype; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30884219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence, RT-PCR, immunoblot of rat and human liver and primary human hepatocytes with antibodies against HJV and TfR2\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization by immunofluorescence in native tissue; replicated finding of basolateral localization; single lab\",\n      \"pmids\": [\"16932966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — systematic mutagenesis with enzymatic cleavage assay; single lab with in silico modeling support\",\n      \"pmids\": [\"25704252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Neogenin siRNA knockdown, soluble neogenin ectodomain competition, dynamin inhibitor, cholesterol depletion with filipin, lysosome inhibitor studies in HepG2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic inhibition approaches; single lab\",\n      \"pmids\": [\"18445598\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Hemojuvelin (HJV) is a GPI-anchored membrane protein that functions primarily in hepatocytes as a co-receptor for BMP ligands (BMP-2, BMP-4, BMP-6), assembling with BMP type I receptors (ALK2/ALK3) and type II receptors (ActRIIA/BMPRII) in a complex scaffolded by neogenin to activate SMAD1/5/8 phosphorylation and transcription of the iron hormone hepcidin; soluble HJV, released by proprotein convertase (furin, at the RNRR site) or by the serine protease matriptase-2/TMPRSS6 (at Arg121/Arg326), acts as a decoy receptor that competes with membrane HJV for BMP ligands and suppresses hepcidin; iron loading promotes membrane HJV retention while iron deficiency increases soluble HJV shedding; HFE, TfR2, and HJV form a multi-protein membrane complex for coordinated iron sensing; and in skeletal muscle HJV additionally suppresses TGF-β1/Smad2/3 signaling by directly interacting with TGF-β receptor II, a mechanistically distinct function from its hepatic BMP co-receptor role.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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 [#0, #21]. 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 [#0, #3]. 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 [#5, #20]. 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 [#21, #22]. 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 [#17, #26, #27]. 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 [#4, #6, #14, #19]. Iron status governs this balance, with iron loading retaining membrane HJV and suppressing release of soluble forms [#1, #6, #12]. HFE and TfR2 form a multi-protein membrane complex with HJV, and genetic epistasis places HFE and HJV in a common hepcidin-regulatory pathway [#16, #25]. 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 [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Stable HJV transfection, reciprocal Co-IP, GPI-anchor and iron-accumulation assays in HEK293 cells\",\n      \"pmids\": [\"16103117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of neogenin binding for hepcidin not yet defined\", \"Did not link HJV to BMP signaling\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown, recombinant soluble HJV treatment of primary hepatocytes, iron titration\",\n      \"pmids\": [\"15998830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for shedding unknown\", \"Molecular target of soluble HJV not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Hjv-mutant mice with iron overload and low hepcidin established HJV as a genetically essential upstream regulator of hepcidin, separate from inflammatory pathways.\",\n      \"evidence\": \"Hjv-mutant mouse, expression analysis, LPS inflammation model\",\n      \"pmids\": [\"16075058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signaling pathway not resolved\", \"Cell-autonomous vs systemic contribution untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying HJV as a BMP co-receptor that upregulates hepcidin defined its core molecular mechanism and connected disease mutations to signaling defects.\",\n      \"evidence\": \"BMP signaling and luciferase reporter assays, Hfe2-/- hepatocytes, mutant analysis\",\n      \"pmids\": [\"16604073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific BMP ligands and receptors not yet enumerated\", \"Role of neogenin in signaling unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pulse-chase, cell-surface labeling, glycosylation analysis, immunofluorescence in muscle cells and liver tissue\",\n      \"pmids\": [\"16868025\", \"16932966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of heterodimer in signaling untested\", \"TfR2 co-localization not yet shown to be a direct interaction\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"PC inhibitors, RNRR-site mutagenesis, neogenin siRNA/overexpression, holo-Tf dose-response, in vivo iron-deficient rat\",\n      \"pmids\": [\"17869549\", \"17331953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether furin product is the physiological decoy in vivo unresolved\", \"Mechanism by which neogenin promotes shedding not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Primary murine hepatocytes, holo/apo-transferrin treatment, pathway inhibition, siRNA\",\n      \"pmids\": [\"17540841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between transferrin sensing and HJV not biochemically defined\", \"Single primary-hepatocyte system\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying matriptase-2 (TMPRSS6) as a protease that cleaves membrane HJV to suppress hepcidin defined a key negative regulatory enzyme of the pathway.\",\n      \"evidence\": \"Cleavage assays, MASK active-site mutant, Co-IP interaction mapping, zebrafish in vivo model\",\n      \"pmids\": [\"18976966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact cleavage residues not yet mapped\", \"Functional properties of the soluble product not characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"BMP ligand binding and receptor co-transfection signaling in hepatoma cells, neogenin siRNA, hepcidin reporters\",\n      \"pmids\": [\"18326817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the receptor complex not determined\", \"Apparent dispensability of neogenin here conflicts with later in vivo data\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Recombinant protein binding assays, neogenin domain-deletion mapping, affinity measurements\",\n      \"pmids\": [\"18335997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of simultaneous binding not tested here\", \"Affinities of competing interactions not ranked\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Oligosaccharide (Endo H/PNGase F) analysis, neogenin siRNA, cholesterol/dynamin/lysosome inhibitors, mutant expression in HeLa/HepG2\",\n      \"pmids\": [\"19029439\", \"17264300\", \"18445598\", \"18384687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise sequence of cleavage and trafficking steps still partly inferred\", \"Single-lab trafficking conclusions\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping disease-mutant defects to either impaired BMP-2 binding or impaired neogenin binding showed that distinct mutations disrupt distinct molecular interactions of HJV.\",\n      \"evidence\": \"BMP-2 and cell-surface neogenin binding assays for wild-type and mutant HJV\",\n      \"pmids\": [\"18287331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional hepcidin output of each mutant not measured here\", \"In vivo correlation lacking\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Hepcidin promoter reporter mutagenesis, neogenin siRNA in HepG2, in vivo soluble neogenin fragment in mice\",\n      \"pmids\": [\"19229506\", \"19564337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conflict with prior report that neogenin was dispensable for signaling\", \"SMAD occupancy of BMP-REs not directly shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Neogenin mutant mice, HJV secretion assays, HJV Arg-residue mutagenesis, BMP6 binding and hepcidin readouts\",\n      \"pmids\": [\"20065295\", \"20937842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exact cleavage residue not unified across studies\", \"Relative in vivo contribution of furin vs matriptase-2 products unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tissue-specific knockout and AAV reconstitution established that hepatic HJV is necessary and sufficient for iron homeostasis, acting principally by potentiating BMP6 signaling.\",\n      \"evidence\": \"Liver- and muscle-specific Hjv knockout mice, AAV2/8 hepatocyte reconstitution in Hjv-/-, hepcidin and phospho-Smad readouts\",\n      \"pmids\": [\"21748766\", \"21493799\", \"20363739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of muscle HJV not addressed here\", \"BMP6 mRNA regulation found independent of HJV, leaving the sensing input upstream of HJV open\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Glycerol gradient sedimentation, Co-IP and domain mapping in HuH7; neogenin siRNA, Co-IP, glycan analysis of MT2 cleavage\",\n      \"pmids\": [\"22728873\", \"22893705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and dynamics of the complexes unknown\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Hfe-/-;Hjv-/- and Hjv-/-;Bmp6-/- double knockout mice, Smad phosphorylation, hepcidin and iron measurements\",\n      \"pmids\": [\"25609138\", \"25608116\", \"26406355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of HJV-independent BMP6 signaling unresolved\", \"Sex-specific differences not mechanistically explained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapping TMPRSS6 cleavage to HJV residues 121 and 326 and the role of R121 in heterodimer rearrangement refined the proteolytic processing model of HJV.\",\n      \"evidence\": \"Arg-to-Ala mutagenesis, TMPRSS6 cleavage assays, N-terminal FLAG fragment analysis, molecular dynamics on RGMb structure\",\n      \"pmids\": [\"25704252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with earlier Arg288/Arg774C mapping incomplete\", \"In vivo relevance of individual sites untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Neogenin- and BMP-binding HJV mutants in Hjv-/- mice, neogenin–ALK3 Co-IP, furin-site mutant in vivo, phospho-Smad readouts\",\n      \"pmids\": [\"27072365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How neogenin connects HJV to ALK3 mechanistically not fully resolved here\", \"Decoy function of soluble HJV not addressed in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conventional and conditional Hjv knockout, mdx and aged-mouse overexpression, HJV–TβRII Co-IP, phospho-Smad2/3, reporter and functional muscle assays\",\n      \"pmids\": [\"30884219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of HJV–TβRII interaction unknown\", \"Relationship to HJV's GPI-anchored processing in muscle unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Hepatocyte-specific Neo1 conditional knockout, Neo1-L1046E and Hjv-A183R mutant reconstitution, Co-IP, Neo1 cytoplasmic-domain cleavage analysis\",\n      \"pmids\": [\"33824974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease cleaving the neogenin cytoplasmic domain not identified\", \"How truncated neogenin scaffold engages ALK3/SMAD not fully detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 28]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 22]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 12, 29, 19]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 22]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 6, 15]}\n    ],\n    \"complexes\": [\n      \"HJV-neogenin-BMP receptor (ALK3) signaling complex\",\n      \"HFE-TfR2-HJV iron-sensing complex\",\n      \"neogenin-matriptase-2(TMPRSS6)-HJV ternary complex\"\n    ],\n    \"partners\": [\n      \"NEO1\",\n      \"TMPRSS6\",\n      \"FURIN\",\n      \"BMP6\",\n      \"BMP2\",\n      \"HFE\",\n      \"TFR2\",\n      \"TGFBR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}