BMP6

Summary: BMP6 signaling can repress smooth-muscle transcriptional programs in a defined cell context.

Reason: PMID:17030628 corroborates a ligand-mediated transcriptional effect: BMP2/4/6 treatment of rat vascular smooth-muscle cells precedes MSX induction and reduced smooth-muscle marker expression. Mouse 10T1/2 promoter experiments and MSX/myocardin/SRF interaction assays are separate mechanistic layers; they do not establish BMP6 DNA binding or transcription-factor activity. Retain the downstream regulatory process as non-core. The observed MGI donor graph links this term to PMID:19252488, whose accessible abstract does not independently resolve the particular repression endpoint; the corroborating experiment is not presented as that original donor source or as proof of the exact historical Ensembl snapshot.

Summary: BMP6 signaling can repress smooth-muscle transcriptional programs in a defined cell context.

Reason: PMID:17030628 corroborates a ligand-mediated transcriptional effect: BMP2/4/6 treatment of rat vascular smooth-muscle cells precedes MSX induction and reduced smooth-muscle marker expression. Mouse 10T1/2 promoter experiments and MSX/myocardin/SRF interaction assays are separate mechanistic layers; they do not establish BMP6 DNA binding or transcription-factor activity. Retain the downstream regulatory process as non-core. The observed MGI donor graph links this term to PMID:19252488, whose accessible abstract does not independently resolve the particular repression endpoint; the corroborating experiment is not presented as that original donor source or as proof of the exact historical Ensembl snapshot.

Summary: Secreted murine BMP6 induced endochondral bone formation in a gain-of-function model.

Reason: PMID:8089189 used murine Vgr-1/BMP6-expressing CHO tumors in nude mice and documented host mesenchymal cartilage and bone formation. Retain the TAS developmental consequence, distinct from the molecular ligand activity and without relabeling it as a human loss-of-function experiment.

Summary: Bone formation and osteoblast differentiation are supported outcomes of BMP6 signaling.

Reason: The orthology transfer is consistent with recombinant-ligand experiments in human mesenchymal cells and bone-formation studies in rodents. These tissue-level outcomes are retained as context-specific roles of the extracellular ligand; the original rat donor experiment is not independently re-audited.

Summary: Bone formation and osteoblast differentiation are supported outcomes of BMP6 signaling.

Reason: The orthology transfer is consistent with recombinant-ligand experiments in human mesenchymal cells and bone-formation studies in rodents. These tissue-level outcomes are retained as context-specific roles of the extracellular ligand; the original rat donor experiment is not independently re-audited.

Summary: Retain the curated eye-development contribution in the mouse chimeric-allele context.

Reason: The observed MGI donor graph assigns eye development by IGI to PMID:16154126. Primary MGI records identify a Bmp7/Bmp6 chimeric allele, kidney expression from the engineered Bmp7 locus, and a compound-genotype record with no abnormal phenotype detected. The inspected pages do not independently expose the individual organ assays, and the full paper was inaccessible. This decision explicitly defers to MGI's organ-specific experimental curation in that complementation context; it does not claim independent verification of the organ endpoint, exact chimeric-protein boundaries, or physiological necessity of endogenous BMP6. The BMP4-focused title is not evidence of a wrong-gene annotation.

Summary: Retain the curated kidney-development contribution in the mouse chimeric-allele context.

Reason: The observed MGI donor graph assigns kidney development by IGI to PMID:16154126. Primary MGI records identify a Bmp7/Bmp6 chimeric allele, kidney expression from the engineered Bmp7 locus, and a compound-genotype record with no abnormal phenotype detected. The inspected pages do not independently expose the individual organ assays, and the full paper was inaccessible. This decision explicitly defers to MGI's organ-specific experimental curation in that complementation context; it does not claim independent verification of the organ endpoint, exact chimeric-protein boundaries, or physiological necessity of endogenous BMP6. The BMP4-focused title is not evidence of a wrong-gene annotation.

Summary: BMP6 increases endothelial-cell yield in a defined mouse progenitor assay, supporting context-specific proliferation.

Reason: The observed mouse donor PMID:20406889 includes a BMP6 experiment despite its BMP9-focused title. Its Results and Figure 3B caption report increased cell number after two days in mouse embryonic-stem-cell-derived VEGFR2-positive progenitors treated with BMP6 at 360 ng/mL together with VEGF at 30 ng/mL in serum-free medium. Retain the authors' proliferation interpretation as non-core, without claiming a BMP6-specific cell-cycle measurement, excluding a survival contribution, or generalizing to adult endothelium. PMID:17119124 independently supports proliferation of BMP6-treated mouse endothelial cells. Most ALK1, adult-endothelial and in vivo experiments in the donor paper concern BMP9 and are not reassigned to BMP6.

Summary: BMP6 promotes development of insulin-positive epithelial colonies in a fetal-pancreas culture model.

Reason: The abstract explicitly uses E15.5 mouse pancreatic cells with laminin-1. It supports a developmental response to ligand in vitro, not a claim that BMP6 is an endocrine-cell structural component or that these were human pancreatic cells.

Summary: BMP6 contributes to cytokine activity in an experimentally active BMP2/BMP6 complex.

Reason: Preserve contributes_to. Recombinant heterodimer experiments and GO-CAM 66e382fb00001786 support the complex-level ligand activity; they do not establish obligatory endogenous heterodimer composition.

Summary: BMP6 binds the erythroferrone ligand trap.

Reason: The cell-free competition assay and signaling experiments support the ERFE interaction. Preserve the mouse ERFE partner Q6PGN1. No more specific BMP6 molecular-function term is established here; sequestration is the activity of ERFE, not BMP6. The correct but broad interaction is retained outside the core function.

Summary: The reported interaction with ALK3 is BMP receptor binding.

Reason: The primary indexed main Results of PMID:31800957, read online and documented in the notes, report BMP6 binding to ALK3/BMPR1A as a positive control. The normal publication cache is citation-only. The immutable UniProt record independently records this receptor interaction and supplies the in-repository excerpt below. Preserve the original mouse receptor accession and evidence code; receptor binding is distinct from downstream receptor-knockdown effects, and supplementary reagent images were not inspected.

Proposed replacements: BMP receptor binding

Summary: The reported interaction with ALK2 is BMP receptor binding.

Reason: The primary indexed main Results of PMID:31800957, read online and documented in the notes, report BMP6 binding to ALK2/ACVR1 as a positive control. The normal publication cache is citation-only. The immutable UniProt record independently records this receptor interaction and supplies the in-repository excerpt below. Preserve the original mouse receptor accession and evidence code; receptor binding is distinct from downstream receptor-knockdown effects, and supplementary reagent images were not inspected.

Proposed replacements: BMP receptor binding

Summary: BMP6 physically interacts with erythroferrone.

Reason: The primary ligand-binding experiments support the mouse ERFE interaction Q6PGN1. Retain this specific observed interaction under its broad source term because no defensible specific BMP6 activity replacement has been established; do not assign ERFE-mediated sequestration to BMP6.

Summary: Extracellular activity is conserved and directly appropriate for secreted BMP6.

Reason: The PAINT inference agrees with BMP6 secretion and extracellular ligand experiments. The target appearing among descendant evidence is legitimate support, not circularity. No challenge to the ancestral node placement is warranted.

Summary: BMP6 acts as a secreted extracellular ligand.

Reason: The electronic location annotation agrees with the immutable UniProt record and secretion experiments. Retain the seeded GO:0005576 term.

Summary: Wild-type BMP6 secretion is supported by human propeptide-variant experiments.

Reason: The abstract reports defective secretion for selected mutant constructs relative to normal BMP6. This supports extracellular location; it does not establish that every propeptide variant is pathogenic.

Summary: The ligand acts extracellularly in the receptor-binding and hepcidin-response experiments.

Reason: Retain NAS as supplied. The source and GO-CAM context support extracellular activity without upgrading the annotation to an independently verified localization assay.

Summary: The iron-homeostasis function is established, but this source does not directly assay the annotated process.

Reason: The complete cached main Results and Methods of PMID:29695288 compare wildtype and p.Q118dup BMP6 localization and secretion in CHO and SK-HEP-1 cells, alongside patient genotyping and allele-frequency analysis. They do not experimentally connect a BMP6 perturbation to intracellular iron regulation. The paper discusses the established BMP6-hepcidin pathway using earlier references. Mark this source-specific IDA process assignment as exceeding the experiments reported; a benign variant result does not contradict the wildtype ligand function. The other iron-homeostasis assertions and GO-CAM pathway interpretation remain supported.

Summary: BMP6 ligand signaling contributes to the modeled iron-homeostasis pathway.

Reason: The receptor-dependent hepcidin response and GO-CAM 66e382fb00001786 support participation in the curated causal pathway. The biochemical experiments do not themselves quantify intracellular iron. Extracellular location does not disqualify a signaling ligand from this process.

Summary: The conserved iron-regulatory signaling role is consistent with this curator-transferred process.

Reason: Retain the manual mouse ortholog transfer in the context of BMP6-driven hepcidin regulation and the existing iron-homeostasis GO-CAM models. This is participation through signaling, not iron transport or binding by BMP6.

Summary: BMP6 contributes to inflammatory signaling in experimentally defined macrophage contexts.

Reason: The observed mouse donor PMID:12151307 reports BMP2/4/6 expression and SMAD1/5 signaling during allergic airway inflammation; this is expression evidence rather than an independently verified BMP6-specific airway perturbation. PMID:19191909 separately tests BMP6 treatment and receptor perturbation in murine RAW264.7 cells, demonstrating iNOS and TNF-alpha induction. The reported confirmation in primary mouse peritoneal macrophages and human THP-1 cells concerns proliferation and receptor expression, not every inflammatory-mediator or receptor-perturbation experiment. This corroborates a context-specific inflammatory contribution without establishing a universal pro-inflammatory effect, transferring macrophage results to airway epithelia, or resolving the separate bacteremia-associated immune-response annotation.

Summary: The accessible source reports association with bacteremia, leaving the mechanistic immune role unresolved.

Reason: PMID:16886151 associates BMP6 polymorphisms with bacteremia in sickle-cell anemia. Its accessible abstract is insufficient to adjudicate the curated IMP process assertion. Preserve the original annotation pending full-text review; no wrong-gene or misattribution claim is made.

Summary: Retain the PAINT-supported developmental role outside the core ligand function.

Reason: Heart development is a tissue-specific outcome. The IBA embodies a curator judgment at PTN008528324; the donor count alone is not a reason to reject it, and no target-specific loss or contradictory evidence was identified. The phylogenetic node was not independently re-curated.

Summary: Growth-factor activity describes the core extracellular signaling function of BMP6.

Reason: Recombinant BMP6 activates receptor-dependent BMP signaling and cellular differentiation responses. This corroborates the electronic activity assignment without assigning the receptor kinase activity to the ligand.

Summary: BMP6 increased DNA synthesis in cultured human periodontal ligament cells.

Reason: PMID:15516325 reports dose-dependent DNA synthesis. Retain the NAS proliferative consequence in that cell context rather than making it a universal growth response.

Summary: Tissue development is a broad downstream role of the morphogen.

Reason: Bone and pancreatic developmental experiments support the broad biological outcome, while the core molecular activity is extracellular ligand signaling.

Summary: Iron-responsive BMP6 production contributes to physiological feedback.

Reason: Retain the rat orthology-based response annotation as regulatory context for the ligand pathway. This does not mean secreted BMP6 directly senses or binds iron; the original donor experiment has not been independently audited.

Summary: BMP6 increases a signaling target transcript in endothelial cells.

Reason: PMID:26598555 measures BMP6-induced ID1 mRNA and its reduction after VE-cadherin knockdown. This is an indirect transcriptional consequence mediated through receptors and SMADs, not transcription-factor activity of BMP6.

Summary: Exercise-associated BMP6 induction is documented, but the original activity-response assertion remains unresolved.

Reason: PMID:23198877 independently documents Bmp6 RNA and protein induction in exercised rats and mechanically stimulated osteochondral constructs. These observations establish regulated ligand abundance without isolating BMP6 participation in the response. The exact original RGD-to-human donor-citation chain has not been recovered, so this independently located expression study cannot establish that the source assertion overinterpreted its evidence or lacked other supporting experiments. Preserve uncertainty while retaining separately supported BMP signaling and tissue-development annotations.

Summary: BMP6 promotes matrix mineralization in primary human mesenchymal cells.

Reason: The Results and Methods of PMID:18436533 document recombinant BMP6 treatment and dose-dependent Alizarin red staining. Retain the differentiation outcome; BMP6 does not itself catalyze mineral deposition.

Summary: The inherited BMP-ligand signaling role is supported by direct BMP6 experiments.

Reason: The PAINT node PTN008528320 agrees with human BMP6 receptor-dependent signaling. The target among descendant evidences is expected, not circular.

Summary: BMP6 induces receptor-dependent signaling in human mesenchymal cells.

Reason: Receptor RNA interference and ID1 induction in PMID:18436533 directly establish a BMP6 ligand response. Receptor utilization depends on cell context; the hMSC results do not exclude receptor interactions demonstrated elsewhere.

Summary: BMP6 activates canonical BMP signaling in human endothelial cells.

Reason: PMID:26598555 measures SMAD1/5 phosphorylation and ID1 responses, with ALK2 and VE-cadherin perturbation. BMP6 initiates the pathway while receptors perform phosphorylation.

Summary: BMP6-containing ligand drives receptor-dependent BMP signaling.

Reason: Recombinant ligand and receptor-perturbation experiments support the hepcidin response. The existing complex GO-CAM distinguishes ligand, receptor and transcriptional roles.

Summary: The electronic BMP-signaling annotation agrees with direct ligand experiments.

Reason: BMP6 is a signaling ligand, with pathway participation independently corroborated in human mesenchymal, endothelial and hepatoma-derived cells.

Summary: BMP6 is an endogenous HJV-dependent BMP ligand in hepatoma-derived cells.

Reason: PMID:18326817 identifies BMP2, BMP4 and BMP6 in HJV-dependent hepcidin signaling. The ligand is distinguished from HJV and the receptor kinases.

Summary: BMP6 pretreatment potentiates selected LPS-induced endothelial activation readouts.

Reason: PMID:27647829 directly tests BMP6 pretreatment of human blood-outgrowth endothelial cells at 50 ng/mL for 16 hours, followed by LPS at 100 ng/mL for four hours, and reports increased surface E-selectin, VCAM-1 and ICAM-1. Retain this positive modulation as non-core and context-specific. Its BMP9 TLR4/ALK1, flow-adhesion and mouse-neutrophil experiments are not assigned to BMP6. This paper postdates the original human ISS annotation and is independent corroboration. The observed MGI donor PMID:19252488 reports preserved inflammatory hepcidin induction despite reduced basal hepcidin in Bmp6-null mice; preserved fold induction does not establish unchanged absolute LPS-stimulated expression or refute all positive BMP6 contributions.

Summary: BMP6 pretreatment potentiates selected LPS-induced endothelial activation readouts.

Reason: PMID:27647829 directly tests BMP6 pretreatment of human blood-outgrowth endothelial cells at 50 ng/mL for 16 hours, followed by LPS at 100 ng/mL for four hours, and reports increased surface E-selectin, VCAM-1 and ICAM-1. Retain this positive modulation as non-core and context-specific. Its BMP9 TLR4/ALK1, flow-adhesion and mouse-neutrophil experiments are not assigned to BMP6. This paper postdates the original human ISS annotation and is independent corroboration. The observed MGI donor PMID:19252488 reports preserved inflammatory hepcidin induction despite reduced basal hepcidin in Bmp6-null mice; preserved fold induction does not establish unchanged absolute LPS-stimulated expression or refute all positive BMP6 contributions.

Summary: A functional vesicle localization is not established by the reviewed evidence.

Reason: Secretion does not exclude transient or specialized vesicle localization, and located_in does not assert that BMP6 performs an intrinsic vesicle function. The exact rat localization assay underlying this transfer remains unresolved. General secretory transit is insufficient to verify the source-specific location, but it is also not evidence that the annotation is erroneous. Retain UNDECIDED pending the donor localization evidence.

Summary: Magnesium-dependent Bmp6 expression is documented, but the transferred response annotation remains unresolved.

Reason: In the independently reviewed rat study PMID:21736832, magnesium deficiency increases hepatic iron and Bmp6 expression, but hepcidin and the BMP-responsive Id1 readout do not increase; several BMP receptor transcripts decrease. Ligand induction therefore does not establish an effective BMP response in this experiment. The original donor-citation chain remains unverified, and the independently located study neither proves the specific transferred process nor excludes other supporting evidence. Retain uncertainty without assigning direct magnesium sensing to BMP6.

Summary: Chondrocyte differentiation is consistent with BMP6-induced endochondral development.

Reason: Retain this orthology-based tissue response in light of the murine cartilage and bone induction study. It is a developmental consequence of ligand signaling, not an additional molecular activity.

Summary: BMP6 augments angiotensin-II-dependent aldosterone production in human H295R cells.

Reason: PMID:16527843 distinguishes increased CYP11B2 transcription and aldosterone output under angiotensin II from the absence of a corresponding effect under potassium stimulation. Retain this specific endocrine regulatory context.

Summary: The accessible retinoic-acid evidence measures cell-specific Bmp6 expression changes; the original response assertion remains unresolved.

Reason: PMID:8385738 independently reports retinoic-acid-induced Bmp6 expression in rat C26 cells and reduced expression in mouse 10T1/2 cells. The accessible BMP6 endpoint is expression; experiments with other TGF-beta-family ligands cannot be reassigned to BMP6. This does not independently verify BMP6 protein participation in the human response. Because the exact original RGD donor-citation chain remains unverified, it also does not establish overinterpretation or exclude other BMP6 functional experiments. Preserve the original assertion as unresolved.

Summary: BMP6 can be a component of an active BMP2/BMP6 ligand complex.

Reason: Recombinant heterodimer experiments and the curated GO-CAM support this assembly. The generic complex term is retained without inventing a specific GO identifier or asserting obligatory endogenous heterodimer abundance.

Summary: Regulation of cell proliferation is a supported broad signaling outcome.

Reason: Human periodontal-ligament and fetal-mouse pancreas experiments support context-dependent proliferative effects. Keep this broad electronic process outside the core activity.

Summary: BMP6 increases endothelial monolayer permeability.

Reason: PMID:26598555 measures solute flux and electrical resistance in HUVECs and tests ALK2/SRC dependence. Retain this cell-context phenotype; it is not evidence of a permeability channel formed by BMP6.

Summary: Positive regulation of differentiation is a supported broad downstream function.

Reason: Recombinant BMP6 promotes osteoblast differentiation in primary human mesenchymal cells. This supports the broad ARBA process without making every cell lineage a BMP6 target.

Summary: The inspected BMP6 assay does not separately establish increased endothelial differentiation.

Reason: The observed mouse donor PMID:20406889 tests BMP6 during differentiation of VEGFR2-positive progenitors, but the inspected BMP6 endpoint is cell number after two days. Greater endothelial-cell yield does not independently distinguish increased lineage commitment from proliferation or survival of differentiating cells. Retain uncertainty about this distinct differentiation annotation; the paper's BMP9-specific mechanistic experiments cannot fill that gap, and its BMP9-focused title is not grounds to reject the BMP6 assertion.

Summary: BMP6 promotes osteoblast differentiation through receptor-mediated signaling.

Reason: PMID:18436533 documents osteoblast markers and mineralization in primary human mesenchymal cells. This directly supports the IDA row and corroborates the separate rat-orthology row, whose own donor assay is not re-audited.

Summary: BMP6 promotes osteoblast differentiation through receptor-mediated signaling.

Reason: PMID:18436533 documents osteoblast markers and mineralization in primary human mesenchymal cells. This directly supports the IDA row and corroborates the separate rat-orthology row, whose own donor assay is not re-audited.

Summary: BMP6 enhances CYP11B2 transcription in an angiotensin-II-dependent endocrine context.

Reason: The H295R-cell study links extracellular BMP6 signaling with enhanced transcription and aldosterone synthesis. Retain the regulatory process while keeping transcription-factor activity on downstream effectors.

Summary: Positive transcriptional regulation is a conserved downstream consequence of BMP6 signaling.

Reason: Human cell experiments establish increased target transcripts after BMP6 stimulation. These corroborate the transferred process generally, without claiming inspection of each mouse donor assay or direct DNA binding by BMP6.

Summary: BMP6 participates in HJV-dependent hepcidin transcriptional regulation.

Reason: The genetic-interaction annotation is consistent with the ligand/coreceptor pathway in PMID:18326817. This is an indirect transcriptional consequence, distinct from the core extracellular activity.

Summary: Positive transcriptional regulation is a conserved downstream consequence of BMP6 signaling.

Reason: Human cell experiments establish increased target transcripts after BMP6 stimulation. These corroborate the transferred process generally, without claiming inspection of each mouse donor assay or direct DNA binding by BMP6.

Summary: BMP6 increases bone-related gene expression in human periodontal ligament cells.

Reason: The source reports increased osteopontin, BMP2, alkaline phosphatase and osteoprotegerin expression. Retain the NAS transcriptional-regulation context without claiming that BMP6 binds promoters.

Summary: BMP6 can participate in a heterodimeric ligand.

Reason: The original PMID:7811286 abstract does not identify the precise BMP6 heterodimer assay. Retain the curator assertion because the function is independently corroborated by the BMP2/BMP6 experiments in PMID:31800957 and GO-CAM 66e382fb00001786; the original full-text experiment was not reverified.

Summary: Cell development is a broad morphogen-response annotation.

Reason: The pancreatic and osteoblastic developmental assays support this broad consequence, which is less informative than the core ligand function.

Summary: BMP6 promotes epithelial colony development in fetal mouse pancreas culture.

Reason: The source reports epithelial colonies formed with laminin-1 and BMP6. Retain the experimental developmental/proliferative interpretation in this culture context; it is not a general human epithelial proliferation claim.

Summary: BMP6 alters production of secreted bone-related proteins in periodontal ligament cells.

Reason: PMID:15516325 uses transcript and protein assays. Retain its NAS secretion-regulation annotation with curator deference, while noting that the accessible abstract does not separate secretion rate from increased synthesis.

Summary: BMP6 mediates a glucocorticoid-induced osteoblast differentiation response in fetal rat cultures.

Reason: PMID:9202223 independently supplies functional evidence beyond induced transcription: antisense BMP6 reduces secreted BMP6 and glucocorticoid-induced mineralized nodules, and recombinant human BMP6 rescues differentiation. The ligand therefore contributes signaling work in this defined response. Retain the transferred process as a context-specific effect, distinct from intrinsic glucocorticoid binding or a universal response in human tissues. The source rat partner remains unchanged; this corroborating paper is not presented as a separately verified RGD transfer-chain record.

Summary: Systemically administered BMP6 promotes bone formation in ovariectomized rats.

Reason: PMID:16798745 measures skeletal outcomes after exogenous BMP6 treatment. Retain bone development as an experimentally supported tissue response, not a demonstration of all normal developmental requirements.

Summary: BMP6 activates Smad1/5 signaling in pulmonary artery endothelial cells.

Reason: The cached Discussion explicitly describes the BMP6 response despite the BMP9-focused title. Preserve the IDA annotation as ligand-driven positive regulation; BMP6 itself is not a kinase.

Summary: Positive regulation of SMAD signaling is a supported BMP6 ligand function.

Reason: Human endothelial experiments independently corroborate the electronic and manually transferred process annotations. Phosphorylation is performed by receptors downstream of BMP6.

Summary: Positive regulation of SMAD signaling is a supported BMP6 ligand function.

Reason: Human endothelial experiments independently corroborate the electronic and manually transferred process annotations. Phosphorylation is performed by receptors downstream of BMP6.

Summary: BMP6 signaling is a conserved regulator of systemic iron balance.

Reason: The mouse orthology assertions agree with hepcidin regulation and independent Bmp6-deficient mouse studies considered in the notes. The protein functions as an extracellular regulatory ligand, not an iron transporter.

Summary: BMP6-dependent hepcidin regulation supports systemic iron homeostasis.

Reason: PMID:26582087 combines human association with transfected-cell secretion, signaling and hepcidin defects for selected propeptide substitutions. Accept the biological process without upgrading variant pathogenicity or the ClinGen Limited disease association.

Summary: Retain the systemic iron-homeostasis process while distinguishing gene function from variant interpretation.

Reason: PMID:28335084 reports human variants and in-silico modeling; the accessible abstract does not establish functional effects of every variant. The process is independently supported by BMP6-dependent hepcidin signaling. No definitive Mendelian or variant-level conclusion follows from this annotation.

Summary: The gene-level iron-regulatory role is supported, with variant-specific limitations.

Reason: PMID:32464486 reports a homozygous truncating variant, a missense VUS and another previously described allele in a sequencing cohort. Preserve the curator process assignment using established hepcidin biology; do not convert the reported variant classifications into independently verified functional measurements.

Summary: BMP6 signaling is a conserved regulator of systemic iron balance.

Reason: The mouse orthology assertions agree with hepcidin regulation and independent Bmp6-deficient mouse studies considered in the notes. The protein functions as an extracellular regulatory ligand, not an iron transporter.

Summary: BMP6 binds BMP receptors to initiate signaling.

Reason: The PMID:7811286 abstract describes binding of other BMP family members but does not identify the exact BMP6 reagent or assay. Preserve the experimental curator assertion because BMP6 receptor binding is independently corroborated by the primary online experiments in PMID:31800957 and the immutable UniProt interaction record. The BMP2/BMP4-focused title is not grounds for claiming misattribution.

Summary: BMP receptor binding is an established ligand function of BMP6.

Reason: The ARBA assignment is independently corroborated by receptor-binding experiments and the curated UniProt interaction record. It does not imply receptor kinase activity.

Summary: Mechanical stimulation induces BMP6 abundance, but the exact evidence for the transferred response annotation remains unresolved.

Reason: PMID:23198877 independently documents time-dependent Bmp6 induction and associated tissue changes in mechanically stimulated chondrocyte/osteoblast constructs, with concordant observations in exercising rats. Conditioned-medium effects and parallel induction of multiple BMPs do not isolate BMP6 participation in this experiment. The original RGD-to-human donor-citation chain remains unverified, so the independent expression evidence cannot establish that the source assertion is overinterpreted or has no other experimental basis. Retain uncertainty without disputing established BMP6 ligand activity or bone and cartilage roles.

Summary: Iron-responsive regulation of BMP6 is part of the physiological feedback context.

Reason: Retain the electronic and curator-transferred mouse response annotations without treating the secreted ligand as an intracellular iron sensor. The exact original donor assays have not been independently re-audited.

Summary: Iron-responsive regulation of BMP6 is part of the physiological feedback context.

Reason: Retain the electronic and curator-transferred mouse response annotations without treating the secreted ligand as an intracellular iron sensor. The exact original donor assays have not been independently re-audited.

Summary: BMP6 contributes to the ligand/coreceptor response system in hepatoma-derived cells.

Reason: PMID:18326817 supports endogenous BMP6 involvement in HJV-dependent signaling and hepcidin responses. Retain the source process, while the core activity is the ligand initiating signaling rather than a separate intracellular sensor of BMP.

Summary: BMP6 increases intracellular signaling through receptor-dependent pathways.

Reason: PMID:26598555 measures c-Src activation, SMAD phosphorylation and downstream expression. Retain this broad process as a consequence of ligand activity, without assigning those enzymatic activities to BMP6.

Summary: BMP6 stimulation disrupts adherens-junction organization in HUVECs.

Reason: The primary Results document altered VE-cadherin distribution and junction architecture. This is a context-specific signaling outcome mediated through receptor and cellular machinery.

Summary: Regulation of organismal development is a broad morphogen role.

Reason: Bone and tissue-development experiments support this high-level process, which does not define an additional molecular function.

Summary: BMP6 signaling reduces VE-cadherin-mediated endothelial adhesion.

Reason: The Results document VE-cadherin internalization, c-Src-dependent phosphorylation and barrier changes in human endothelial cells. BMP6 triggers these changes through receptors; it is not itself the adhesion molecule or kinase.

Summary: BMP6 can enhance aldosterone output in a specific adrenal-cell signaling context.

Reason: The orthology transfer is consistent with the human H295R response to angiotensin II and BMP6. Preserve the distinction from potassium-stimulated secretion, which was unaffected in that experiment.