BMP4 is a secreted, disulfide-linked growth factor of the TGF-beta superfamily. Proteolytic maturation of its precursor produces a ligand that engages type I and type II BMP receptor complexes, initiating receptor-mediated SMAD1/5/8 signaling and context-dependent noncanonical responses. Co-receptors and extracellular antagonists modulate receptor use and signal strength, while the prodomain can bind fibrillin matrix components. BMP4 directs cell-fate choices and tissue patterning in many embryonic organs and regulates proliferation, survival, migration and differentiation according to cell type, developmental stage and signaling environment.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:9187146 Bone morphogenetic proteins (BMPs) as regulators of dorsal f... | KEEP AS NON CORE | Summary: BMP4 represses a forebrain gene-expression program. Reason: PMID:9187146 reports inhibition of Bf1 expression by exogenous BMP4/BMP2 in embryonic telencephalic explants. Retain the curated transcription-regulation assertion as a downstream developmental effect, without assigning BMP4 DNA binding or RNA-polymerase activity; the inspected abstract does not resolve the intervening transcriptional mechanism. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Conserved downstream repression of transcription is supported. Reason: The mouse-ortholog transfer is consistent with BMP4-mediated repression of Bf1 in telencephalic explants (PMID:9187146). BMP4 acts as an extracellular signal; repression of a particular gene program is a context-dependent outcome rather than a separate core molecular activity. The exact donor experiment was not independently reconstructed. |
| GO:0001649 osteoblast differentiation | IDA PMID:17720811 Noncanonical Wnt-4 signaling enhances bone regeneration of m... | UNDECIDED | Summary: The exact BMP4 osteoblast experiment remains unverified. Reason: The accessible PMID:17720811 abstract foregrounds Wnt4-induced osteogenesis. Other BMP4 studies support osteoblast differentiation, but the BMP4-specific assay underlying this source assertion was not accessible. This is an evidence-access limit, not evidence of a wrong-gene attribution. |
| GO:0001649 osteoblast differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 promotes osteoblastic differentiation in appropriate cultures. Reason: The electronic prediction is independently consistent with recombinant BMP4 experiments in C2C12 cells and primary human mesenchymal stem cells (PMIDs:14749725 and 18436533). Osteoblastic differentiation is one tissue-specific consequence of BMP receptor signaling. |
| GO:0001657 ureteric bud development | IDA PMID:12141440 BMPs and BMP receptors in mouse metanephric development: in ... | KEEP AS NON CORE | Summary: BMP4 regulates ureteric-bud development in explant culture. Reason: PMID:12141440 directly tests BMP4 in mouse metanephric explants and reports inhibition of ureteric branching at the tested concentrations. Retain the developmental role without implying that BMP4 always promotes bud growth. |
| GO:0001658 branching involved in ureteric bud morphogenesis | IDA PMID:12631064 Evidence that bone morphogenetic protein 4 has multiple biol... | KEEP AS NON CORE | Summary: BMP4 has context-dependent effects on urinary-tract branching and morphogenesis. Reason: PMID:12631064 combines Bmp4 heterozygous mice with recombinant-BMP4 explant experiments and distinguishes metanephric from periureteral responses. Retain this curated developmental annotation; the inspected abstract supports broader urinary-tract morphogenesis rather than enumerating every branch endpoint. |
| GO:0001822 kidney development | IMP PMID:18305125 SIX2 and BMP4 mutations associate with anomalous kidney deve... | KEEP AS NON CORE | Summary: BMP4 contributes to kidney development. Reason: PMID:18305125 combines human renal-hypodysplasia observations with functional testing in zebrafish. This supports a developmental signaling role; it does not independently determine the current clinical classification of each reported variant. |
| GO:0001823 mesonephros development | IEP PMID:18437684 Involvement of FGF and BMP family proteins and VEGF in early... | UNDECIDED | Summary: Expression in developing kidney does not resolve the precise mesonephric role. Reason: PMID:18437684 reports BMP2/4 immunoreactivity in human developing kidneys. The IEP assertion is preserved, but the inspected expression study does not establish the exact causal mesonephros-development assignment sufficiently for a firm functional decision. |
| GO:0001934 positive regulation of protein phosphorylation | IDA PMID:14749725 Endogenous TGF-beta signaling suppresses maturation of osteo... | KEEP AS NON CORE | Summary: BMP4 stimulation increases downstream SMAD phosphorylation. Reason: Selected PMID:14749725 Results report rapid SMAD1/5 phosphorylation after recombinant BMP4 exposure in C2C12 cells. BMP4 activates receptor signaling; the receptors perform the phosphorylation. Retain this broad downstream regulatory endpoint outside the core molecular-activity summary. |
| GO:0001938 positive regulation of endothelial cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 can stimulate endothelial proliferation. Reason: The ortholog-derived prediction is corroborated by BMP4-induced endothelial proliferation and migration in PMID:17992660. Its direction is cell-context dependent and should not be generalized to pulmonary artery smooth-muscle cells, where inhibitory responses are reported. |
| GO:0001958 endochondral ossification | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific endochondral-ossification donor evidence remains unverified. Reason: BMP4 has well-supported osteogenic signaling activity, but the precise mouse donor experiment for endochondral ossification was not inspected. General in vitro osteogenesis and BMP2-dependent SCUBE3 skeletal phenotypes do not alone verify this more specific transfer. |
| GO:0001958 endochondral ossification | ISS GO_REF:0000024 | UNDECIDED | Summary: The specific endochondral-ossification donor evidence remains unverified. Reason: BMP4 has well-supported osteogenic signaling activity, but the precise mouse donor experiment for endochondral ossification was not inspected. General in vitro osteogenesis and BMP2-dependent SCUBE3 skeletal phenotypes do not alone verify this more specific transfer. |
| GO:0002043 blood vessel endothelial cell proliferation involved in sprouting angiogenesis | IDA PMID:18787191 BMPER is an endothelial cell regulator and controls bone mor... | UNDECIDED | Summary: The proliferation endpoint within sprouting needs the specific experiment. Reason: PMID:18787191 supports BMP4/BMPER-dependent endothelial sprouting, migration and SMAD1/5 activation. Its accessible abstract does not separately establish endothelial cell division within sprouting angiogenesis; that exact assay remains unverified, without disputing the curator. |
| GO:0002062 chondrocyte differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The precise chondrocyte-differentiation transfer remains unresolved. Reason: The mouse donor experiment underlying this assertion was not inspected. Selected SCUBE3 chondrocyte experiments in PMID:33308444 use BMP2, so their specific results cannot be silently transferred to BMP4. |
| GO:0002062 chondrocyte differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: The precise chondrocyte-differentiation transfer remains unresolved. Reason: The mouse donor experiment underlying this assertion was not inspected. Selected SCUBE3 chondrocyte experiments in PMID:33308444 use BMP2, so their specific results cannot be silently transferred to BMP4. |
| GO:0002244 hematopoietic progenitor cell differentiation | IDA PMID:15451575 FLRG, member of the follistatin family, a new player in hema... | UNDECIDED | Summary: The BMP4-specific hematopoietic progenitor result is not exposed by the abstract. Reason: PMID:15451575 mentions a BMP4 comparison but emphasizes BMP2/activin commitment effects. The precise BMP4 differentiation experiment supporting this IDA assertion was not available; preserve the source rather than infer a misattribution. |
| GO:0002320 lymphoid progenitor cell differentiation | IMP PMID:12421925 Bone morphogenetic protein 2/4 signaling regulates early thy... | KEEP AS NON CORE | Summary: BMP4 regulates lymphoid progenitor differentiation. Reason: PMID:12421925 reports BMP4 inhibition of thymocyte differentiation and proliferation with enhanced survival. A role in differentiation does not require a positive direction; this is a non-core immune-development context. |
| GO:0002573 myeloid leukocyte differentiation | IEA GO_REF:0000117 | UNDECIDED | Summary: The myeloid differentiation prediction lacks verified BMP4-specific support here. Reason: The ARBA assignment is plausible for a pleiotropic morphogen, but the exact BMP4 intervention in the associated macrophage/monocyte literature was not accessible. Neither the term nor a negative judgment is inferred from the article title. |
| GO:0003007 heart morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Inherited involvement in heart morphogenesis is consistent with BMP4 biology. Reason: The PAINT assertion represents inheritance from a curated ancestral node, not a pairwise donor vote. BMP4 itself among the supporting descendants is expected, not circular. Chick anterior-heart-field BMP4 perturbations in PMID:20702560 provide target-specific developmental grounding; the complete PAINT node history was not reconstructed. |
| GO:0003007 heart morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 contributes to cardiac morphogenesis through progenitor signaling. Reason: PMID:20702560 shows BMP4 promoting cardiomyocyte differentiation in chick anterior-heart-field tissue through antagonism of FGF signaling. Retain cardiac morphogenesis as a developmental outcome, without assigning BMP4 the downstream transcription-factor work. |
| GO:0003007 heart morphogenesis | IMP PMID:20702560 BMP-mediated inhibition of FGF signaling promotes cardiomyoc... | KEEP AS NON CORE | Summary: BMP4 contributes to cardiac morphogenesis through progenitor signaling. Reason: PMID:20702560 shows BMP4 promoting cardiomyocyte differentiation in chick anterior-heart-field tissue through antagonism of FGF signaling. Retain cardiac morphogenesis as a developmental outcome, without assigning BMP4 the downstream transcription-factor work. |
| GO:0003129 heart induction | IEA GO_REF:0000117 | UNDECIDED | Summary: Heart induction is not resolved separately from later progenitor differentiation. Reason: The accessible PMID:20702560 evidence concerns the shift of existing anterior-heart-field progenitors toward cardiomyocyte differentiation. The distinct early induction endpoint and the relevant source experiment were not verified. Preserve the assertion pending that evidence. |
| GO:0003129 heart induction | IMP PMID:20702560 BMP-mediated inhibition of FGF signaling promotes cardiomyoc... | UNDECIDED | Summary: Heart induction is not resolved separately from later progenitor differentiation. Reason: The accessible PMID:20702560 evidence concerns the shift of existing anterior-heart-field progenitors toward cardiomyocyte differentiation. The distinct early induction endpoint and the relevant source experiment were not verified. Preserve the assertion pending that evidence. |
| GO:0003139 secondary heart field specification | IMP PMID:20702560 BMP-mediated inhibition of FGF signaling promotes cardiomyoc... | UNDECIDED | Summary: Secondary-heart-field specification needs the precise source experiment. Reason: PMID:20702560 directly supports differentiation of anterior-heart-field progenitors, but the inspected abstract does not distinguish initial field specification from later maturation. The more specific assignment remains undecided rather than being rejected. |
| GO:0003148 outflow tract septum morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 contributes to outflow-tract and membranous-septum morphogenesis. Reason: Selected primary passages from the mouse conditional Bmp4 study PMID:18924235 support outflow-tract and membranous-septum defects. They corroborate this developmental transfer, while the exact GO donor edge was not independently joined. The additional paper is cached and linked as corroborating mouse evidence, not as a direct human experiment or a reconstructed GO donor edge. |
| GO:0003148 outflow tract septum morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BMP4 contributes to outflow-tract and membranous-septum morphogenesis. Reason: Selected primary passages from the mouse conditional Bmp4 study PMID:18924235 support outflow-tract and membranous-septum defects. They corroborate this developmental transfer, while the exact GO donor edge was not independently joined. The additional paper is cached and linked as corroborating mouse evidence, not as a direct human experiment or a reconstructed GO donor edge. |
| GO:0003149 membranous septum morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 contributes to outflow-tract and membranous-septum morphogenesis. Reason: Selected primary passages from the mouse conditional Bmp4 study PMID:18924235 support outflow-tract and membranous-septum defects. They corroborate this developmental transfer, while the exact GO donor edge was not independently joined. The additional paper is cached and linked as corroborating mouse evidence, not as a direct human experiment or a reconstructed GO donor edge. |
| GO:0003149 membranous septum morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BMP4 contributes to outflow-tract and membranous-septum morphogenesis. Reason: Selected primary passages from the mouse conditional Bmp4 study PMID:18924235 support outflow-tract and membranous-septum defects. They corroborate this developmental transfer, while the exact GO donor edge was not independently joined. The additional paper is cached and linked as corroborating mouse evidence, not as a direct human experiment or a reconstructed GO donor edge. |
| GO:0003150 muscular septum morphogenesis | ISS NOT GO_REF:0000024 | KEEP AS NON CORE | Summary: The muscular-septum NOT assertion is supported within the conditional anterior-heart-field mouse model. Reason: In PMID:18924235, neonatal histology after Mef2c-AHF-Cre conditional Bmp4 deletion showed no apparent muscular-septum phenotype, despite a distinct membranous-septum defect. Retain the mouse-derived NOT transfer as non-core within this conditional tissue and developmental context. The result does not establish that BMP4 is dispensable for muscular-septum morphogenesis in every model or developmental window. Supporting Evidence: |
| GO:0003151 outflow tract morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 contributes to outflow-tract and membranous-septum morphogenesis. Reason: Selected primary passages from the mouse conditional Bmp4 study PMID:18924235 support outflow-tract and membranous-septum defects. They corroborate this developmental transfer, while the exact GO donor edge was not independently joined. The additional paper is cached and linked as corroborating mouse evidence, not as a direct human experiment or a reconstructed GO donor edge. |
| GO:0003163 sinoatrial node development | NAS PMID:26786210 The formation and function of the cardiac conduction system. | UNDECIDED | Summary: The sinoatrial-node claim is not verifiable from the accessible review abstract. Reason: PMID:26786210 is a review of cardiac-conduction development, but its inspected abstract does not expose the BMP4-specific sinoatrial-node evidence. Retain the NAS source unchanged and leave the precise assignment undecided. |
| GO:0003180 aortic valve morphogenesis | IEA GO_REF:0000107 | UNDECIDED | Summary: Valve-specific donor experiments remain unverified. Reason: A broad cardiac or outflow-tract role does not by itself establish this particular valve-morphogenesis transfer. The mouse donor experiment was not inspected, so the source assertion is retained without confident acceptance or removal. |
| GO:0003180 aortic valve morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: Valve-specific donor experiments remain unverified. Reason: A broad cardiac or outflow-tract role does not by itself establish this particular valve-morphogenesis transfer. The mouse donor experiment was not inspected, so the source assertion is retained without confident acceptance or removal. |
| GO:0003184 pulmonary valve morphogenesis | IEA GO_REF:0000107 | UNDECIDED | Summary: Valve-specific donor experiments remain unverified. Reason: A broad cardiac or outflow-tract role does not by itself establish this particular valve-morphogenesis transfer. The mouse donor experiment was not inspected, so the source assertion is retained without confident acceptance or removal. |
| GO:0003184 pulmonary valve morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: Valve-specific donor experiments remain unverified. Reason: A broad cardiac or outflow-tract role does not by itself establish this particular valve-morphogenesis transfer. The mouse donor experiment was not inspected, so the source assertion is retained without confident acceptance or removal. |
| GO:0003197 endocardial cushion development | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact endocardial-cushion developmental evidence remains unresolved. Reason: Conditional cardiac phenotypes are relevant but do not by themselves verify each cushion endpoint, tissue and stage. The precise mouse donor experiment for this term was not joined to the source assertion. |
| GO:0003197 endocardial cushion development | ISS GO_REF:0000024 | UNDECIDED | Summary: The exact endocardial-cushion developmental evidence remains unresolved. Reason: Conditional cardiac phenotypes are relevant but do not by themselves verify each cushion endpoint, tissue and stage. The precise mouse donor experiment for this term was not joined to the source assertion. |
| GO:0003198 epithelial to mesenchymal transition involved in endocardial cushion formation | ISS NOT GO_REF:0000024 | KEEP AS NON CORE | Summary: The cushion-EMT NOT assertion is supported for initial EMT in the conditional mouse explant assay. Reason: PMID:18924235 compared Mef2c-AHF-Cre conditional Bmp4 knockout and control outflow-tract explants collected at E9.5 and cultured on collagen for 48 hours. Mesenchymal-cell migration showed no obvious difference, and cushions had begun forming at E10.5; the explant result was reported without displayed data. Retain the NOT transfer as non-core for initial EMT in this assay, not for later cushion expansion or remodeling, which were defective. Supporting Evidence: |
| GO:0003215 cardiac right ventricle morphogenesis | ISS NOT GO_REF:0000024 | KEEP AS NON CORE | Summary: The right-ventricle NOT assertion is supported for myocardial morphology in the conditional mouse model. Reason: PMID:18924235 reports no apparent right-ventricular myocardial phenotype in neonatal hearts after Mef2c-AHF-Cre conditional Bmp4 deletion, although the Cre lineage contributes to that tissue. Retain the mouse-derived NOT transfer as non-core with this anatomical and developmental limit. The observation does not establish normality of every ventricular function or exclude an earlier BMP4 requirement. Supporting Evidence: |
| GO:0003277 apoptotic process involved in endocardial cushion morphogenesis | ISS NOT GO_REF:0000024 | KEEP AS NON CORE | Summary: The cushion-apoptosis NOT assertion is supported in proximal outflow cushions at the measured embryonic stages. Reason: In PMID:18924235, TUNEL staining detected no difference in apoptosis between Mef2c-AHF-Cre conditional Bmp4 knockout embryos and littermate controls in proximal outflow-tract endocardial cushions at E10.5 and E12.5. Retain the NOT transfer as non-core for these tissues, stages and assay. Reduced cushion cell number and defective remodeling do not imply an apoptosis change, and this negative result does not cover all cardiac apoptosis. Supporting Evidence: |
| GO:0003279 cardiac septum development | TAS PMID:18076106 Mutations in GATA4, NKX2.5, CRELD1, and BMP4 are infrequentl... | UNDECIDED | Summary: The septal-development reference is citation-only in the available cache. Reason: PMID:18076106 has no substantive indexed abstract in the authenticated normal cache. Its title does not establish a BMP4 functional experiment, penetrance or mechanism. The TAS assertion remains undecided until relevant source content is accessible. |
| GO:0003323 type B pancreatic cell development | IDA PMID:11865031 Bone morphogenetic proteins promote development of fetal pan... | KEEP AS NON CORE | Summary: BMP4 promotes development of fetal pancreatic epithelial cultures containing insulin-positive cells. Reason: PMID:11865031 tests BMP4/5/6 with laminin-1 in dissociated E15.5 mouse pancreas cultures and reports epithelial colonies with localized insulin-positive cells. Retain this developmental phenotype without claiming complete mature beta-cell function or a universal endocrine differentiation response. |
| GO:0005125 cytokine activity | IBA GO_REF:0000033 | ACCEPT | Summary: BMP4 is an extracellular cytokine/growth-factor ligand. Reason: The PAINT cytokine assertion fits BMP4 receptor activation and the production GO-CAM models. Its inclusion of BMP4 among experimentally grounded descendants is expected. There is no target-specific loss or divergence evidence challenging inheritance of this signaling activity. |
| GO:0005125 cytokine activity | IDA PMID:14749725 Endogenous TGF-beta signaling suppresses maturation of osteo... | ACCEPT | Summary: Recombinant BMP4 elicits receptor-mediated signaling and differentiation responses. Reason: PMID:14749725 tests recombinant human BMP4, including C2C12 SMAD phosphorylation and osteogenic responses. This is direct functional support for BMP4 as a signaling ligand rather than as a receptor kinase. Supporting Evidence: PMID:14749725 BMP-4 induced the production of ALP in hMSCs |
| GO:0005125 cytokine activity | IEA GO_REF:0000117 | ACCEPT | Summary: Cytokine activity describes the core secreted signaling function. Reason: The electronic assignment agrees with direct BMP4 stimulation experiments and extracellular BMP4 cytokine nodes in the two inspected GO-CAM models. This broad ligand activity is consistent with the more specific growth-factor synthesis. |
| GO:0005515 protein binding | IPI PMID:10748465 Cerberus-like is a secreted BMP and nodal antagonist not ess... | KEEP AS NON CORE | Summary: BMP4 binds a secreted Cerberus-family antagonist. Reason: PMID:10748465 reports specific extracellular BMP binding by mouse Cerberus-like, the source partner O55233. Preserve the supported interaction as non-core; no precise BMP4 molecular-activity replacement was established for antagonist binding. BMP4 does not acquire the antagonist's inhibitory activity, and broadness alone is not a reason to REMOVE the assertion. |
| GO:0005515 protein binding | IPI PMID:12045205 Functional analysis of bone morphogenetic protein type II re... | MODIFY | Summary: The BMPR2 interaction is BMP receptor binding. Reason: The source partner Q13873 is BMPR2. PMID:12045205 measures radiolabeled BMP4 binding with wild-type and mutant receptors and connects receptor trafficking to BMP/SMAD responses. Refine generic protein binding to the existing specific receptor-binding term while retaining this source tuple. Proposed replacements: BMP receptor binding Supporting Evidence: PMID:12045205 reduced binding of (125)I-BMP4 |
| GO:0005515 protein binding | IPI PMID:18339631 Targeting of bone morphogenetic protein growth factor comple... | MODIFY | Summary: The BMP4 prodomain binds fibrillin extracellular-matrix components. Reason: PMID:18339631 Table 3 reports BMP4-prodomain binding to FBN1 rF23 and FBN2 rF86 (34 and 25 nM). Extracellular matrix binding fits these fragment assays. Rotary-shadowed complexes are BMP7-specific; separate BMP4 tissue co-immunolocalization does not establish direct binding to assembled microfibrils or universal control of ligand availability. Proposed replacements: extracellular matrix binding |
| GO:0005515 protein binding | IPI PMID:18339631 Targeting of bone morphogenetic protein growth factor comple... | MODIFY | Summary: The BMP4 prodomain binds fibrillin extracellular-matrix components. Reason: PMID:18339631 Table 3 reports BMP4-prodomain binding to FBN1 rF23 and FBN2 rF86 (34 and 25 nM). Extracellular matrix binding fits these fragment assays. Rotary-shadowed complexes are BMP7-specific; separate BMP4 tissue co-immunolocalization does not establish direct binding to assembled microfibrils or universal control of ligand availability. Proposed replacements: extracellular matrix binding |
| GO:0005515 protein binding | IPI PMID:20505824 Agrin binds BMP2, BMP4 and TGFbeta1. | MODIFY | Summary: BMP4 binds an agrin extracellular-matrix fragment. Reason: PMID:20505824 tests the N-terminal portion of rat agrin, source partner P25304, using surface plasmon resonance and reporter assays. Extracellular matrix binding captures this interaction more specifically. Preserve the rat fragment context; BMP4 does not thereby acquire agrin's neuromuscular receptor-clustering activity. Proposed replacements: extracellular matrix binding |
| GO:0005515 protein binding | IPI PMID:20860622 DIP2 disco-interacting protein 2 homolog A (Drosophila) is a... | UNDECIDED | Summary: The exact BMP4βBMPR1A experiment needs inspection. Reason: PMID:20860622 includes BMP4 ligand/receptor-binding experiments in its FSTL1 analysis, but the precise source pair with P36894 and assay construct were not verified from the accessible abstract. Keep the partner and IPI assertion; the title is not evidence of a wrong-gene annotation. |
| GO:0005515 protein binding | IPI PMID:21054789 WFIKKN1 and WFIKKN2 bind growth factors TGFΞ²1, BMP2 and BMP4... | UNDECIDED | Summary: The BMP4βBMPR1A source pair is not fully resolved by the accessible WFIKKN study. Reason: PMID:21054789 distinguishes physical binding from inhibition of signaling and reports no BMP4 reporter inhibition under the tested conditions. That does not refute BMP4 receptor binding. The precise P36894 pair and assay underlying this IPI row remain unverified. |
| GO:0005515 protein binding | IPI PMID:33308444 SCUBE3 loss-of-function causes a recognizable recessive deve... | MODIFY | Summary: BMP4 binds the SCUBE3 co-receptor. Reason: Selected PMID:33308444 Results report co-precipitation of Myc-BMP4 and FLAG-SCUBE3 after co-overexpression in HEK293T cells, with complementary BMP4 signaling experiments. SCUBE3 is an auxiliary receptor-associated signal modulator, fitting co-receptor binding. Retain the tagged-overexpression limit; CUB-domain mapping in the paper was BMP2-specific. Proposed replacements: co-receptor binding |
| GO:0005515 protein binding | IPI PMID:8413626 The daf-4 gene encodes a bone morphogenetic protein receptor... | MODIFY | Summary: Human BMP4 binds the nematode BMP receptor DAF-4 in a heterologous-cell assay. Reason: PMID:8413626 reports human BMP4 binding to DAF-4 expressed in monkey COS cells, supporting BMP receptor binding rather than generic protein binding. NCBI Gene 175781 maps the source partner G8JY02 to a daf-4 product. The exact tested construct has not been matched to every accession; that product-level uncertainty does not prevent refining the demonstrated BMP4 molecular function. Preserve this distinct partner tuple and the cross-species assay context. Proposed replacements: BMP receptor binding Supporting Evidence: PMID:8413626 daf-4 receptor binds human BMP-2 and BMP-4. |
| GO:0005515 protein binding | IPI PMID:8413626 The daf-4 gene encodes a bone morphogenetic protein receptor... | MODIFY | Summary: Human BMP4 binds the nematode BMP receptor DAF-4 in a heterologous-cell assay. Reason: PMID:8413626 reports human BMP4 binding to DAF-4 expressed in monkey COS cells, supporting BMP receptor binding rather than generic protein binding. NCBI Gene 175781 maps the source partner P50488 to a daf-4 product. The exact tested construct has not been matched to every accession; that product-level uncertainty does not prevent refining the demonstrated BMP4 molecular function. Preserve this distinct partner tuple and the cross-species assay context. Proposed replacements: BMP receptor binding Supporting Evidence: PMID:8413626 daf-4 receptor binds human BMP-2 and BMP-4. |
| GO:0005515 protein binding | IPI PMID:8413626 The daf-4 gene encodes a bone morphogenetic protein receptor... | MODIFY | Summary: Human BMP4 binds the nematode BMP receptor DAF-4 in a heterologous-cell assay. Reason: PMID:8413626 reports human BMP4 binding to DAF-4 expressed in monkey COS cells, supporting BMP receptor binding rather than generic protein binding. NCBI Gene 175781 maps the source partner Q8ITX8 to a daf-4 product. The exact tested construct has not been matched to every accession; that product-level uncertainty does not prevent refining the demonstrated BMP4 molecular function. Preserve this distinct partner tuple and the cross-species assay context. Proposed replacements: BMP receptor binding Supporting Evidence: PMID:8413626 daf-4 receptor binds human BMP-2 and BMP-4. |
| GO:0005515 protein binding | IPI PMID:8752214 The Spemann organizer signal noggin binds and inactivates bo... | KEEP AS NON CORE | Summary: BMP4 binds the extracellular antagonist noggin. Reason: PMID:8752214 directly reports high-affinity nogginβBMP4 binding and blockade of BMP4 receptor engagement. Retain this supported generic interaction as non-core because a more specific BMP4 activity term was not established. BMP4 is the bound signaling ligand, not the antagonist. Supporting Evidence: PMID:8752214 noggin protein binds BMP4 with high affinity |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Extracellular localization is conserved and central to BMP4 signaling. Reason: The PAINT localization inference fits the signal peptide, extracellular receptor engagement and both inspected BMP4 GO-CAM activities. Supporting descendants include BMP4 itself as legitimate experimental grounding, not circular propagation. |
| GO:0005576 extracellular region | IDA PMID:16604073 Bone morphogenetic protein signaling by hemojuvelin regulate... | ACCEPT | Summary: BMP4 functions as a secreted extracellular ligand. Reason: The UniProt signal peptide and extracellular localization agree with soluble-ligand receptor experiments and the BMP4 signaling models. The source assertion is consistent with this core location; this does not imply that every precursor molecule has already been secreted. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: BMP4 functions as a secreted extracellular ligand. Reason: The UniProt signal peptide and extracellular localization agree with soluble-ligand receptor experiments and the BMP4 signaling models. The source assertion is consistent with this core location; this does not imply that every precursor molecule has already been secreted. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: BMP4 functions as a secreted extracellular ligand. Reason: The UniProt signal peptide and extracellular localization agree with soluble-ligand receptor experiments and the BMP4 signaling models. The source assertion is consistent with this core location; this does not imply that every precursor molecule has already been secreted. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2396399 | ACCEPT | Summary: The fibrillin-binding reaction places BMP4 extracellularly. Reason: Reactome R-HSA-2396399 and the BMP4-prodomain/fibrillin biochemical evidence support an extracellular interaction. Retain this location without extending the fragment-binding experiment into an untested physiological sequestration claim. |
| GO:0005576 extracellular region | TAS Reactome:R-NUL-9831901 | ACCEPT | Summary: The Grem1βBMP4 binding reaction is extracellular. Reason: The cached Reactome R-NUL-9831901 entry describes rat Grem1 interacting with human BMP4. Preserve that mixed-species orphan-reaction context rather than interpreting the Homo sapiens summary header as evidence that both participants are human. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | UNDECIDED | Summary: The ER-lumen reaction assignment needs BMP4-specific evidence. Reason: BMP4 is a secretory precursor, so ER transit is plausible. The cached FAM20C reaction is a kinase/substrate summary and does not expose the BMP4-specific localization experiment. Topology is neither proof of this exact reaction assignment nor a basis for rejecting ER passage; retain the TAS row undecided. |
| GO:0007498 mesoderm development | IDA PMID:8752214 The Spemann organizer signal noggin binds and inactivates bo... | KEEP AS NON CORE | Summary: BMP4 regulates mesodermal patterning. Reason: PMID:8752214 distinguishes ventral mesoderm-promoting BMP activity from noggin-mediated dorsalization. Retain mesoderm development as a context-specific morphogen effect, separate from BMP4's core receptor-ligand activity. |
| GO:0008083 growth factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Growth-factor activity is the principal molecular function of BMP4. Reason: The InterPro-based assignment is corroborated by direct BMP4 receptor binding and by ligand-stimulated proliferation or differentiation in multiple experimental systems. A growth factor can inhibit growth in some cells while promoting differentiation or growth in others; BMP4 is not uniformly mitogenic. |
| GO:0008201 heparin binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact heparin-binding donor experiment was not verified. Reason: The mouse-derived electronic assertion is retained, but extracellular location and protein binding do not independently demonstrate heparin binding. The specific donor assay and tested BMP4 species remain to be inspected. |
| GO:0008284 positive regulation of cell population proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: BMP4 can promote proliferation in responsive cell contexts. Reason: The PAINT assertion is consistent with direct target evidence in periodontal-ligament and endothelial cultures. BMP4 among the descendant sources is expected, not circular. Opposite responses in smooth-muscle or neural cultures do not refute this context-dependent inherited capacity. |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:15516325 Effect of bone morphogenetic proteins-4, -5 and -6 on DNA sy... | KEEP AS NON CORE | Summary: BMP4 increases DNA synthesis in human periodontal-ligament cultures. Reason: PMID:15516325 reports BMP4-enhanced BrdU incorporation in human periodontal-ligament cells. This supports the source proliferation-regulation assertion in that culture context, without implying a universal positive effect on every cell type. |
| GO:0008284 positive regulation of cell population proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A positive proliferative response is consistent with target-specific BMP4 experiments. Reason: The mouse transfer is corroborated by human periodontal-ligament DNA-synthesis measurements (PMID:15516325) and endothelial responses (PMID:17992660). Keep the effect non-core and cell-context dependent; the exact ortholog donor experiment was not reconstructed. |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:9187146 Bone morphogenetic proteins (BMPs) as regulators of dorsal f... | KEEP AS NON CORE | Summary: BMP4 inhibits proliferation in embryonic telencephalic explants. Reason: PMID:9187146 directly reports locally reduced cell proliferation after BMP exposure in embryonic forebrain explants. This coexists with pro-proliferative effects elsewhere and is a developmental response rather than an invariant ligand property. |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:20702560 BMP-mediated inhibition of FGF signaling promotes cardiomyoc... | KEEP AS NON CORE | Summary: BMP4 signaling shifts cardiac progenitors from proliferation toward differentiation. Reason: PMID:20702560 reports BMP4 antagonism of FGF signaling in chick anterior-heart-field progenitors, with MSX1-dependent repression and cardiomyocyte differentiation. Retain the downstream inhibitory proliferation effect without assigning BMP4 the intracellular transcriptional work. |
| GO:0009791 post-embryonic development | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | UNDECIDED | Summary: A post-embryonic-development assignment is not resolved by the accessible prenatal-lung study. Reason: PMID:8674409 primarily describes embryonic lung misexpression and abnormal function at birth. The exact post-embryonic endpoint behind this IDA assertion was not inspected. A birth phenotype alone does not establish the detailed developmental interval. |
| GO:0010453 regulation of cell fate commitment | IDA PMID:18823971 GDF3 is a BMP inhibitor that can activate Nodal signaling on... | KEEP AS NON CORE | Summary: BMP4 changes embryonic ectodermal fate in an experimental assay. Reason: Selected PMID:18823971 Results and Methods use recombinant human BMP4 in frog animal-cap experiments, shifting dissociated cells from neural-default toward epidermal fate, with GDF3 antagonism. This is direct ligand activity in a cross-species developmental assay, not a claim that the human experiment occurred in vivo. |
| GO:0010467 gene expression | IEA GO_REF:0000107 | MODIFY | Summary: BMP4 regulates gene expression downstream of its receptors. Reason: BMP4 is a secreted signal rather than a component of transcription or translation machinery. Target-specific studies demonstrate both increased and decreased gene expression, including opposite miRNA changes in PMID:28124060. Refine this broad process assignment to the two supported regulatory directions without claiming direct DNA or RNA binding. Proposed replacements: positive regulation of gene expression negative regulation of gene expression |
| GO:0010628 positive regulation of gene expression | IDA PMID:24906886 MicroRNA-363 negatively regulates the left ventricular deter... | KEEP AS NON CORE | Summary: BMP4 promotes a HAND2-associated expression response in cardiac differentiation. Reason: PMID:24906886 connects BMP4 exposure with HAND2 expression in human embryonic-stem-cell cardiac differentiation. This is downstream gene-expression regulation; HAND2, not extracellular BMP4, supplies transcription-factor activity. |
| GO:0010628 positive regulation of gene expression | IDA PMID:28124060 Bone morphogenetic protein 4 regulates microRNAs miR-494 and... | KEEP AS NON CORE | Summary: BMP4 changes endothelial miRNA expression in opposite directions for different targets. Reason: PMID:28124060 reports increased miR-126-5p and decreased miR-494 after BMP4 stimulation of HUVECs. Retain the corresponding source direction as a downstream expression effect. Abundance changes alone do not establish the specific transcriptional versus processing mechanism. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive gene-expression regulation is supported in BMP4-responsive cells. Reason: The mouse transfer agrees with target-specific induction of HAND2 and miR-126-5p in PMIDs:24906886 and 28124060. This is a context-dependent downstream response, not intrinsic transcription-factor activity of BMP4. |
| GO:0010629 negative regulation of gene expression | IDA PMID:28124060 Bone morphogenetic protein 4 regulates microRNAs miR-494 and... | KEEP AS NON CORE | Summary: BMP4 changes endothelial miRNA expression in opposite directions for different targets. Reason: PMID:28124060 reports increased miR-126-5p and decreased miR-494 after BMP4 stimulation of HUVECs. Retain the corresponding source direction as a downstream expression effect. Abundance changes alone do not establish the specific transcriptional versus processing mechanism. |
| GO:0010718 positive regulation of epithelial to mesenchymal transition | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific positive EMT transfer needs donor-context verification. Reason: BMP4 can affect epithelial fate, but generic BMP signaling or epithelial differentiation does not establish positive EMT in the source mouse context. The exact donor experiment was not inspected, and lung BMP/gremlin results should not be extrapolated to every EMT model. |
| GO:0021537 telencephalon development | IDA PMID:9187146 Bone morphogenetic proteins (BMPs) as regulators of dorsal f... | KEEP AS NON CORE | Summary: BMP4 participates in dorsal telencephalic development. Reason: PMID:9187146 combines spatial expression with BMP4/BMP2 explant effects on Msx1/Bf1 expression, proliferation and apoptosis. Retain the developmental role as non-core; BMP4's molecular work is extracellular signaling. |
| GO:0021537 telencephalon development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 participates in dorsal telencephalic development. Reason: PMID:9187146 combines spatial expression with BMP4/BMP2 explant effects on Msx1/Bf1 expression, proliferation and apoptosis. Retain the developmental role as non-core; BMP4's molecular work is extracellular signaling. |
| GO:0022408 negative regulation of cell-cell adhesion | IEA GO_REF:0000117 | UNDECIDED | Summary: The negative cell-cell adhesion prediction lacks a verified BMP4-specific assay. Reason: The ARBA source is retained, but neither altered tissue patterning nor an EMT-related phenotype alone identifies the relevant adhesion assay or mechanism. No precise replacement is asserted without that evidence. |
| GO:0030224 monocyte differentiation | IDA PMID:21149635 Monocytic cells derived from human embryonic stem cells and ... | UNDECIDED | Summary: The exact BMP4 intervention in myeloid differentiation remains inaccessible. Reason: PMID:21149635 concerns human embryonic-stem-cell-derived macrophage biology, but the inspected abstract does not expose the BMP4 experiment underlying this monocyte/macrophage differentiation assertion. Preserve the source; a different focal gene or cell type in the abstract is not a misattribution finding. |
| GO:0030225 macrophage differentiation | IDA PMID:21149635 Monocytic cells derived from human embryonic stem cells and ... | UNDECIDED | Summary: The exact BMP4 intervention in myeloid differentiation remains inaccessible. Reason: PMID:21149635 concerns human embryonic-stem-cell-derived macrophage biology, but the inspected abstract does not expose the BMP4 experiment underlying this monocyte/macrophage differentiation assertion. Preserve the source; a different focal gene or cell type in the abstract is not a misattribution finding. |
| GO:0030335 positive regulation of cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 can promote cell migration in defined tissue contexts. Reason: The mouse-derived prediction is corroborated by direct periureteral mesenchymal Boyden-chamber migration in PMID:12631064 and endothelial responses in PMID:17992660. Retain the contextual motility outcome separately from the core growth-factor activity. |
| GO:0030501 positive regulation of bone mineralization | IDA PMID:14749725 Endogenous TGF-beta signaling suppresses maturation of osteo... | KEEP AS NON CORE | Summary: BMP4 supports matrix mineralization under osteogenic culture conditions. Reason: Selected PMID:14749725 Results show calcium deposition in human mesenchymal stem cells with BMP4 plus the TGF-beta receptor inhibitor SB431542 in supplemented serum-free medium. Preserve both distinct source assertions and the synergy/medium dependence; the experiment does not show BMP4 alone mineralizing an intact bone. |
| GO:0030501 positive regulation of bone mineralization | IDA PMID:14749725 Endogenous TGF-beta signaling suppresses maturation of osteo... | KEEP AS NON CORE | Summary: BMP4 supports matrix mineralization under osteogenic culture conditions. Reason: Selected PMID:14749725 Results show calcium deposition in human mesenchymal stem cells with BMP4 plus the TGF-beta receptor inhibitor SB431542 in supplemented serum-free medium. Preserve both distinct source assertions and the synergy/medium dependence; the experiment does not show BMP4 alone mineralizing an intact bone. |
| GO:0030501 positive regulation of bone mineralization | IDA PMID:18436533 BMP-2/4 and BMP-6/7 differentially utilize cell surface rece... | KEEP AS NON CORE | Summary: BMP4 promotes mineralization in primary human mesenchymal stem-cell cultures. Reason: PMID:18436533 reports dose-dependent calcium deposits after BMP4 and other BMP treatments, assessed with Alizarin red, unlike differentiation medium alone. This supports the tissue-specific mineralization effect and corroborates the electronic assignment without making mineral deposition a molecular activity of BMP4. |
| GO:0030501 positive regulation of bone mineralization | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 promotes mineralization in primary human mesenchymal stem-cell cultures. Reason: PMID:18436533 reports dose-dependent calcium deposits after BMP4 and other BMP treatments, assessed with Alizarin red, unlike differentiation medium alone. This supports the tissue-specific mineralization effect and corroborates the electronic assignment without making mineral deposition a molecular activity of BMP4. |
| GO:0030509 BMP signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: BMP4 is a conserved initiating ligand of BMP signaling. Reason: The PAINT pathway assignment agrees with direct BMP4 receptor-binding and stimulation experiments and both inspected GO-CAMs. BMP4 is an experimentally grounded descendant in the source list; that is expected and does not undermine the ancestral inference. |
| GO:0030509 BMP signaling pathway | IDA PMID:10748465 Cerberus-like is a secreted BMP and nodal antagonist not ess... | ACCEPT | Summary: Extracellular antagonism of BMP4 demonstrates its role in BMP signaling. Reason: PMID:10748465 describes Cerberus-like binding and antagonism of BMP signaling molecules. Retain BMP4 as the ligand within the pathway; its participation is distinct from the antagonist's inhibitory molecular activity. |
| GO:0030509 BMP signaling pathway | IDA PMID:16816361 Bone morphogenetic protein-4 inhibitor gremlin is overexpres... | ACCEPT | Summary: BMP4 drives signaling opposed by gremlin. Reason: PMID:16816361 directly studies responsiveness to endogenous and exogenous BMP4 in lung fibroblast systems with altered gremlin. The measured ligand-dependent response supports BMP pathway participation, without assigning the accompanying fibrosis phenotype as a separate core function. |
| GO:0030509 BMP signaling pathway | IDA PMID:17244894 Antagonistic effects of bone morphogenetic protein-4 and -7 ... | ACCEPT | Summary: BMP4 activates signaling in mesangial cells. Reason: PMID:17244894 studies BMP4/SMAD signaling in the modulation of aldosterone-induced mesangial mitosis. This is direct ligand-driven BMP-pathway participation even though its growth response is inhibitory. |
| GO:0030509 BMP signaling pathway | IDA PMID:18436533 BMP-2/4 and BMP-6/7 differentially utilize cell surface rece... | ACCEPT | Summary: BMP4 signals through BMP receptors during osteogenic differentiation. Reason: PMID:18436533 tests BMP4 among four BMP ligands in human mesenchymal stem cells and examines receptor utilization and osteogenic output. The core pathway assignment is supported independently of how broadly the mineralization phenotype generalizes. Supporting Evidence: PMID:18436533 Although BMP-2/4 used predominantly BMPR1A for signaling |
| GO:0030509 BMP signaling pathway | IDA PMID:18787191 BMPER is an endothelial cell regulator and controls bone mor... | ACCEPT | Summary: BMP4 stimulates a BMPER-dependent endothelial BMP response. Reason: PMID:18787191 reports BMP4-dependent endothelial signaling and SMAD1/5 activation, with BMPER required in the tested system. This establishes BMP pathway participation while preserving dose and cofactor context. |
| GO:0030509 BMP signaling pathway | IDA PMID:8752214 The Spemann organizer signal noggin binds and inactivates bo... | ACCEPT | Summary: BMP4 receptor engagement initiates BMP signaling. Reason: PMID:8752214 reports direct noggin binding that blocks BMP4 engagement of cell-surface receptors. This supports the ligand's role in the BMP pathway rather than conferring noggin's inhibitory activity on BMP4. |
| GO:0030509 BMP signaling pathway | IDA PMID:9389648 Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-indu... | ACCEPT | Summary: BMP4 elicits receptor/SMAD signaling with the required downstream machinery. Reason: Selected PMID:9389648 Methods and Results use engineered SMAD constructs. In SMAD4-deficient SW480.7 cells, BMP4 alone does not restore the GAL4-SMAD reporter response; transcriptional activation requires rescue by full-length SMAD4 or its C domain. Separate localization assays also use activated BMP type-I receptor cotransfection. Retain BMP-pathway participation with these requirements explicit, rather than presenting an inactive construct as a positive ligand response. Supporting Evidence: PMID:9389648 is rescued by cotransfection of full-length Smad4 |
| GO:0030509 BMP signaling pathway | IMP PMID:17472960 Repulsive guidance molecule RGMa alters utilization of bone ... | ACCEPT | Summary: BMP4 signals through receptor complexes whose use is modulated by RGMa. Reason: PMID:17472960 reports BMP4βRGMa binding and context-dependent utilization of BMPRII versus ActRIIA. This supports BMP4 pathway participation; RGMa is the co-receptor, while BMP4 is the ligand. |
| GO:0030509 BMP signaling pathway | IMP PMID:17992660 Regulation of bone morphogenetic protein signalling in human... | ACCEPT | Summary: BMP4 activates endothelial BMP signaling. Reason: PMID:17992660 reports BMP4-induced endothelial proliferation, migration and SMAD phosphorylation. Retain the core pathway role without conflating endothelial stimulation with the inhibitory smooth-muscle response in other studies. |
| GO:0030509 BMP signaling pathway | IMP PMID:18326817 Hemojuvelin regulates hepcidin expression via a selective su... | ACCEPT | Summary: BMP4 is an endogenous ligand in HJV-mediated BMP signaling. Reason: PMID:18326817 identifies BMP4 among endogenous HJV ligands in hepatoma-derived cells and shows co-receptor-dependent receptor utilization. This supports the pathway annotation without implying that the hepatoma system defines all physiological receptor preferences. |
| GO:0030509 BMP signaling pathway | IMP PMID:20702560 BMP-mediated inhibition of FGF signaling promotes cardiomyoc... | ACCEPT | Summary: BMP4 pathway activity drives anterior-heart-field signaling responses. Reason: PMID:20702560 uses signaling perturbations in chick tissue and identifies BMP4-dependent differentiation responses with FGF-pathway antagonism. The BMP-pathway role is core; its cardiac developmental output is separately retained as non-core. |
| GO:0030509 BMP signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse transfer is consistent with direct BMP4 pathway evidence. Reason: Numerous target-specific receptor and ligand-stimulation studies support the inherited BMP signaling role, and both inspected GO-CAMs place BMP4 cytokine activity within this pathway. No unsupported receptor-catalytic activity is assigned to BMP4. |
| GO:0030513 positive regulation of BMP signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 can reinforce BMP signaling through downstream feedback. Reason: The ortholog-derived regulatory assignment is consistent with the BMP4βmiR-302βBMPRII feedback described in PMID:22988237: reduced miR-302 permits greater receptor expression. Retain the feedback capacity as non-core; simply being the initiating ligand would not by itself establish positive feedback. The precise source donor edge was not independently reconstructed. |
| GO:0030513 positive regulation of BMP signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BMP4 can reinforce BMP signaling through downstream feedback. Reason: The ortholog-derived regulatory assignment is consistent with the BMP4βmiR-302βBMPRII feedback described in PMID:22988237: reduced miR-302 permits greater receptor expression. Retain the feedback capacity as non-core; simply being the initiating ligand would not by itself establish positive feedback. The precise source donor edge was not independently reconstructed. |
| GO:0030858 positive regulation of epithelial cell differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 can promote epithelial differentiation. Reason: Recombinant human BMP4 restores epidermal fate in frog animal-cap experiments in PMID:18823971, and pancreatic epithelial-colony responses are reported in PMID:11865031. These support the broad electronic prediction as a developmental response, without extending it to every epithelial lineage. |
| GO:0032092 positive regulation of protein binding | IDA PMID:23610558 Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor ax... | KEEP AS NON CORE | Summary: BMP4 stimulation promotes association of downstream signaling proteins. Reason: Selected PMID:23610558 Results use BMP4-dependent co-immunoprecipitation and proximity assays involving Ark2C, phosphorylated SMAD1/5/8 and Ski, and describe SMAD-complex assembly. Retain this signaling-regulation endpoint; BMP4 is not itself a nuclear protein-bridging factor, and proximity assays do not prove every pair directly binds. |
| GO:0032967 positive regulation of collagen biosynthetic process | IDA PMID:17720811 Noncanonical Wnt-4 signaling enhances bone regeneration of m... | UNDECIDED | Summary: The BMP4-specific collagen-biosynthesis assay is not accessible. Reason: The PMID:17720811 abstract emphasizes Wnt4-mediated osteogenesis. The exact BMP4 collagen result supporting this source annotation was not inspected. Do not replace the source or reject the curator on the basis of the abstract's emphasis. |
| GO:0033085 negative regulation of T cell differentiation in thymus | IMP PMID:12421925 Bone morphogenetic protein 2/4 signaling regulates early thy... | KEEP AS NON CORE | Summary: BMP4 inhibits thymic T-lineage differentiation and proliferation. Reason: PMID:12421925 reports inhibition of thymocyte differentiation and proliferation with improved survival after BMP4 signaling. Retain the distinct source endpoints as non-core immune-development responses rather than interpreting reduced cell expansion as increased apoptosis. |
| GO:0033088 negative regulation of immature T cell proliferation in thymus | IMP PMID:12421925 Bone morphogenetic protein 2/4 signaling regulates early thy... | KEEP AS NON CORE | Summary: BMP4 inhibits thymic T-lineage differentiation and proliferation. Reason: PMID:12421925 reports inhibition of thymocyte differentiation and proliferation with improved survival after BMP4 signaling. Retain the distinct source endpoints as non-core immune-development responses rather than interpreting reduced cell expansion as increased apoptosis. |
| GO:0035990 tendon cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The tendon or deltoid-tuberosity donor experiment remains unverified. Reason: The exact mouse-transfer study for this specialized musculoskeletal endpoint was not inspected. General BMP4 osteogenesis does not by itself establish tendon differentiation or the anatomical deltoid-tuberosity phenotype; preserve each assertion pending the relevant evidence. |
| GO:0035990 tendon cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: The tendon or deltoid-tuberosity donor experiment remains unverified. Reason: The exact mouse-transfer study for this specialized musculoskeletal endpoint was not inspected. General BMP4 osteogenesis does not by itself establish tendon differentiation or the anatomical deltoid-tuberosity phenotype; preserve each assertion pending the relevant evidence. |
| GO:0035993 deltoid tuberosity development | IEA GO_REF:0000107 | UNDECIDED | Summary: The tendon or deltoid-tuberosity donor experiment remains unverified. Reason: The exact mouse-transfer study for this specialized musculoskeletal endpoint was not inspected. General BMP4 osteogenesis does not by itself establish tendon differentiation or the anatomical deltoid-tuberosity phenotype; preserve each assertion pending the relevant evidence. |
| GO:0035993 deltoid tuberosity development | ISS GO_REF:0000024 | UNDECIDED | Summary: The tendon or deltoid-tuberosity donor experiment remains unverified. Reason: The exact mouse-transfer study for this specialized musculoskeletal endpoint was not inspected. General BMP4 osteogenesis does not by itself establish tendon differentiation or the anatomical deltoid-tuberosity phenotype; preserve each assertion pending the relevant evidence. |
| GO:0039706 co-receptor binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 has experimentally supported co-receptor interactions. Reason: The ARBA assignment is corroborated by the BMP4βSCUBE3 tagged co-precipitation and functional results in PMID:33308444 and by HJV/RGMa pathway evidence. This is a receptor-modulatory interaction supporting the core ligand function, not evidence that BMP4 itself is a co-receptor. |
| GO:0039706 co-receptor binding | IPI PMID:16604073 Bone morphogenetic protein signaling by hemojuvelin regulate... | UNDECIDED | Summary: The exact BMP4βmouse HJV binding assay remains unverified. Reason: The source partner Q7TQ32 and IPI tuple are preserved. PMID:16604073 establishes the HJV/BMP/hepcidin framework, but its abstract does not expose this precise BMP4/partner experiment. Later HJV signaling evidence supports plausibility without substituting for the source-pair assay. |
| GO:0042056 chemoattractant activity | IDA PMID:12631064 Evidence that bone morphogenetic protein 4 has multiple biol... | KEEP AS NON CORE | Summary: BMP4 acts as a chemoattractant for periureteral mesenchymal cells. Reason: PMID:12631064 directly reports a modified Boyden-chamber experiment and accumulation around BMP4-loaded beads. This specific molecular activity is supported, but it is a localized developmental use of BMP4 signaling rather than an independent broadly conserved core function in this synthesis. Supporting Evidence: PMID:12631064 BMP4 can serve as a chemoattractant for periureteral mesenchymal cells |
| GO:0042306 regulation of protein import into nucleus | IDA PMID:22529382 Altered subcellular localization of transcription factor TEA... | UNDECIDED | Summary: BMP4-induced nuclear localization does not resolve the transport mechanism. Reason: The accessible body of PMID:22529382 reports that BMP4 exposure induces TEAD4 nuclear localization in inner embryonic cells and explicitly leaves the mechanism unresolved. This supports altered localization, but the exact import rather than export/retention mechanism behind the source term was not verified. BMP4 is not assigned nuclear transport activity. |
| GO:0042476 odontogenesis | IGI PMID:11023873 BMP4 rescues a non-cell-autonomous function of Msx1 in tooth... | KEEP AS NON CORE | Summary: BMP4 supplies a downstream signal required for tooth development. Reason: PMID:11023873 shows BMP4 rescue of Msx1-deficient tooth germs to enamel and dentin formation after explant culture and kidney-capsule grafting. Retain the genetic developmental relationship; the source Msx1 partner is not asserted to bind BMP4 physically. |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:9187146 Bone morphogenetic proteins (BMPs) as regulators of dorsal f... | KEEP AS NON CORE | Summary: BMP4 can promote apoptosis in neural developmental contexts. Reason: PMID:9187146 reports increased local apoptosis in embryonic telencephalic explants treated with BMP proteins. This supports a context-specific pro-apoptotic response and the broad electronic assignment; it does not contradict BMP4-dependent survival in thymic or renal systems. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 can promote apoptosis in neural developmental contexts. Reason: PMID:9187146 reports increased local apoptosis in embryonic telencephalic explants treated with BMP proteins. This supports a context-specific pro-apoptotic response and the broad electronic assignment; it does not contradict BMP4-dependent survival in thymic or renal systems. |
| GO:0043068 positive regulation of programmed cell death | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | KEEP AS NON CORE | Summary: BMP4 misexpression increases cell death in embryonic lung mesenchyme. Reason: PMID:8674409 reports increased mesenchymal cell death alongside altered growth in transgenic mouse lungs. Retain the perturbation-supported developmental effect, with misexpression and tissue context explicit rather than treating it as universal physiological pro-death signaling. |
| GO:0045603 positive regulation of endothelial cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: Endothelial differentiation is not established by proliferation or migration alone. Reason: The mouse-derived assignment is plausible, but the specific donor differentiation assay was not inspected. BMP4 effects on endothelial proliferation, sprouting or migration do not independently establish initial endothelial lineage differentiation. |
| GO:0045606 positive regulation of epidermal cell differentiation | IDA PMID:18823971 GDF3 is a BMP inhibitor that can activate Nodal signaling on... | KEEP AS NON CORE | Summary: Human BMP4 promotes epidermal differentiation in frog explants. Reason: PMID:18823971 uses recombinant human BMP4 in animal-cap assays and reports recovery of epidermal rather than neural-default fate. This directly supports the source activity in the stated cross-species assay, without inventing a human in vivo phenotype. |
| GO:0045662 negative regulation of myoblast differentiation | IDA PMID:14749725 Endogenous TGF-beta signaling suppresses maturation of osteo... | KEEP AS NON CORE | Summary: BMP4 inhibits myogenic differentiation of C2C12 cells. Reason: Selected PMID:14749725 Results report inhibition of myotube formation by recombinant human BMP4 while osteogenic outputs increase. Retain the direct culture result as a non-core lineage-choice effect. |
| GO:0045669 positive regulation of osteoblast differentiation | IDA PMID:14749725 Endogenous TGF-beta signaling suppresses maturation of osteo... | KEEP AS NON CORE | Summary: BMP4 promotes osteoblast differentiation in responsive cultures. Reason: PMIDs:14749725 and 18436533 directly test BMP4 in C2C12 or primary human mesenchymal stem cells, with ALP and osteogenic differentiation/mineralization readouts. Preserve cell type, medium and co-treatment dependence rather than treating every BMP4 response as osteogenic. |
| GO:0045669 positive regulation of osteoblast differentiation | IDA PMID:18436533 BMP-2/4 and BMP-6/7 differentially utilize cell surface rece... | KEEP AS NON CORE | Summary: BMP4 promotes osteoblast differentiation in responsive cultures. Reason: PMIDs:14749725 and 18436533 directly test BMP4 in C2C12 or primary human mesenchymal stem cells, with ALP and osteogenic differentiation/mineralization readouts. Preserve cell type, medium and co-treatment dependence rather than treating every BMP4 response as osteogenic. |
| GO:0045778 positive regulation of ossification | IDA PMID:14749725 Endogenous TGF-beta signaling suppresses maturation of osteo... | KEEP AS NON CORE | Summary: BMP4 supports an osteogenic program and bone-nodule formation in culture. Reason: PMID:14749725 reports BMP4-dependent osteoblast-associated differentiation and bone-nodule/mineralization responses, enhanced by TGF-beta-pathway inhibition. Retain the source ossification-regulation assertion as an in vitro developmental output rather than a distinct catalytic function. |
| GO:0045786 negative regulation of cell cycle | IDA PMID:11502704 Altered growth responses of pulmonary artery smooth muscle c... | KEEP AS NON CORE | Summary: BMP4 inhibits cell-cycle progression in control pulmonary artery smooth-muscle cultures. Reason: PMID:11502704 reports reduced DNA synthesis/proliferative responses to BMP4, with altered responses in pulmonary-hypertension-derived cells. Preserve this context-dependent inhibitory cell-cycle effect without generalizing it to endothelial cells or all patient isolates. |
| GO:0045839 negative regulation of mitotic nuclear division | IDA PMID:17244894 Antagonistic effects of bone morphogenetic protein-4 and -7 ... | KEEP AS NON CORE | Summary: BMP4 suppresses aldosterone-stimulated mesangial mitosis. Reason: PMID:17244894 directly reports modulation of mesangial mitosis by BMP4/SMAD signaling. Retain the negative mitotic effect in that stimulated-cell context; the extracellular ligand is not part of the mitotic machinery. |
| GO:0045843 negative regulation of striated muscle tissue development | IDA PMID:14749725 Endogenous TGF-beta signaling suppresses maturation of osteo... | MODIFY | Summary: The direct experiment resolves inhibition of myoblast differentiation. Reason: The inspected PMID:14749725 experiment uses C2C12 myotube differentiation, not development of a whole striated-muscle tissue. Refine the broad tissue-development term to the existing directly supported negative regulation of myoblast differentiation, retaining the source evidence. Proposed replacements: negative regulation of myoblast differentiation |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:12631064 Evidence that bone morphogenetic protein 4 has multiple biol... | UNDECIDED | Summary: The precise transcriptional repression experiment remains unverified. Reason: PMID:12631064 reports BMP4 effects on mesenchymal compartments and Pax2/Foxd1 expression patterns. The inspected abstract does not distinguish changed cellular composition or expression from the exact transcriptional-repression assay underlying this IDA row. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:17600318 BMP4 induces HO-1 via a Smad-independent, p38MAPK-dependent ... | UNDECIDED | Summary: HO-1 expression induction does not expose the precise transcription assay. Reason: PMID:17600318 describes BMP4-induced HO-1 expression and MAPK-dependent growth inhibition in pulmonary artery smooth-muscle cells. The accessible abstract does not resolve the transcription-specific experiment behind this assertion; retain it undecided, without rejecting the reported induction. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 promotes downstream transcriptional responses through receptors and SMADs. Reason: BMP4-responsive reporter experiments in PMIDs:12045205 and 9389648 support transcriptional regulation. Retain the broad electronic assignment as downstream signaling, while distinguishing the ligand from receptor kinases and nuclear transcription factors. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:15516325 Effect of bone morphogenetic proteins-4, -5 and -6 on DNA sy... | UNDECIDED | Summary: The polymerase-II-specific assay is not accessible. Reason: PMID:15516325 reports bone-related expression changes and DNA synthesis in BMP4-treated periodontal-ligament cultures. The precise transcription-by-RNA-polymerase-II endpoint is not exposed by the inspected abstract, and increased transcript abundance alone does not resolve its mechanism. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:9187146 Bone morphogenetic proteins (BMPs) as regulators of dorsal f... | KEEP AS NON CORE | Summary: BMP4 induces a forebrain gene-expression program. Reason: PMID:9187146 reports induction of Msx1 in embryonic telencephalic explants after BMP4/BMP2 exposure. Retain the curated downstream transcription-regulation role without assigning BMP4 polymerase or DNA-binding activity; the inspected abstract does not resolve the intermediate mechanism. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:18326817 Hemojuvelin regulates hepcidin expression via a selective su... | KEEP AS NON CORE | Summary: BMP4/HJV signaling regulates hepcidin expression. Reason: PMID:18326817 identifies BMP4 as an endogenous HJV ligand and examines receptor-dependent hepcidin regulation in hepatoma-derived cells. Retain the curated transcriptional output as non-core and distinguish the genetic HJV relationship from direct BMP4 transcription-factor activity. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The ortholog transfer is consistent with BMP4-responsive transcription. Reason: Human BMP4 receptor/SMAD reporter responses and gene-expression induction corroborate this downstream regulatory capacity. The exact mouse donor experiment was not reconstructed; this retention does not assign DNA binding or polymerase activity to the secreted ligand. |
| GO:0048286 lung alveolus development | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | UNDECIDED | Summary: The precise alveolar-development endpoint requires full source inspection. Reason: PMID:8674409 reports distended terminal buds, abnormal air-filled sacs at birth and fewer differentiated Type II cells after BMP4 misexpression. These are relevant lung phenotypes, but the exact alveolus-development assignment and developmental stage were not verified separately. |
| GO:0048392 intermediate mesodermal cell differentiation | IDA PMID:10021330 The surface ectoderm is essential for nephric duct formation... | KEEP AS NON CORE | Summary: BMP4 supplies an inductive signal for intermediate-mesoderm differentiation. Reason: PMID:10021330 reports BMP4-loaded bead rescue of nephric-duct differentiation and marker expression after removal of surface ectoderm. Retain the ligand-mediated differentiation role without guessing an organism that is not specified in the inspected abstract. |
| GO:0048661 positive regulation of smooth muscle cell proliferation | IDA PMID:17600318 BMP4 induces HO-1 via a Smad-independent, p38MAPK-dependent ... | UNDECIDED | Summary: The positive smooth-muscle proliferation assertion needs the actual source experiment. Reason: PMID:17600318 emphasizes BMP4/HO-1-mediated growth inhibition in human pulmonary artery smooth-muscle cells. The full experiment underlying the positive-proliferation row was inaccessible. Preserve the row and investigate its condition or intervention rather than REMOVE an experimental annotation on an abstract-level directional discrepancy. |
| GO:0048662 negative regulation of smooth muscle cell proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 inhibits proliferation in defined smooth-muscle contexts. Reason: PMIDs:11502704 and 17600318 support inhibitory BMP4 responses in pulmonary artery smooth-muscle cultures. This corroborates the ARBA assignment as a context-dependent outcome, not a universal direction of BMP4 action. |
| GO:0048745 smooth muscle tissue development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 contributes to smooth-muscle development around the ureter. Reason: PMID:12631064 reports reduced alpha-SMA-positive periureteral cells in Bmp4 heterozygotes and BMP4-dependent mesenchymal accumulation. This corroborates a developmental role for the ortholog transfer; the exact original mouse donor edge was not reconstructed. |
| GO:0048745 smooth muscle tissue development | IEP PMID:17850284 Immunohistochemical analysis of Sonic hedgehog signalling in... | KEEP AS NON CORE | Summary: BMP4 expression coincides with developing human urinary-tract smooth muscle. Reason: Selected full-text Results in PMID:17850284 directly show BMP4 immunolocalization in mesenchyme coincident with alpha-SMA during human urogenital-sinus muscularization. Retain the IEP annotation as expression-based developmental support, not as a BMP4 perturbation experiment or proof that BMP4 is sufficient for detrusor differentiation. |
| GO:0048745 smooth muscle tissue development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BMP4 contributes to smooth-muscle development around the ureter. Reason: PMID:12631064 reports reduced alpha-SMA-positive periureteral cells in Bmp4 heterozygotes and BMP4-dependent mesenchymal accumulation. This corroborates a developmental role for the ortholog transfer; the exact original mouse donor edge was not reconstructed. |
| GO:0048863 stem cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 regulates differentiation of stem and progenitor populations. Reason: The ortholog-derived broad process is corroborated by BMP4-induced osteogenic differentiation of human mesenchymal stem cells and by human embryonic-stem-cell studies. This is a non-core developmental outcome; it does not imply that BMP4 induces the same fate in every stem-cell population. |
| GO:0048863 stem cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BMP4 regulates differentiation of stem and progenitor populations. Reason: The ortholog-derived broad process is corroborated by BMP4-induced osteogenic differentiation of human mesenchymal stem cells and by human embryonic-stem-cell studies. This is a non-core developmental outcome; it does not imply that BMP4 induces the same fate in every stem-cell population. |
| GO:0050679 positive regulation of epithelial cell proliferation | IDA PMID:11865031 Bone morphogenetic proteins promote development of fetal pan... | UNDECIDED | Summary: Epithelial-colony development alone does not resolve proliferation. Reason: PMID:11865031 reports BMP4-associated development of pancreatic epithelial colonies with insulin-positive regions. The inspected abstract does not distinguish cell division from survival, morphogenesis or differentiation as the cause of colony formation; the exact positive proliferation assay remains unverified. |
| GO:0050918 positive chemotaxis | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Positive chemotaxis follows the experimentally supported chemoattractant activity. Reason: The GO logical inference is consistent with the BMP4 Boyden-chamber and bead experiments in PMID:12631064. Preserve the periureteral mesenchymal context and distinguish directed migration from a general proliferative effect. |
| GO:0051241 negative regulation of multicellular organismal process | IEA GO_REF:0000117 | UNDECIDED | Summary: The broad multicellular-process prediction is not linked to a specific source mechanism. Reason: BMP4 has several genuine inhibitory developmental effects, but the ARBA row does not identify which underlies this very broad assignment. A particular replacement should not be guessed from the many available phenotypes; retain it undecided pending the rule context. |
| GO:0055007 cardiac muscle cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 promotes cardiomyocyte differentiation in a developmental context. Reason: PMID:20702560 reports BMP4-induced myofibrillar gene expression and cardiomyocyte contraction in chick anterior-heart-field progenitors, with FGF-pathway antagonism. Retain the cardiac differentiation/fiber-development outcomes as non-core without implying that BMP4 is a sarcomere component. |
| GO:0055020 positive regulation of cardiac muscle fiber development | IMP PMID:20702560 BMP-mediated inhibition of FGF signaling promotes cardiomyoc... | KEEP AS NON CORE | Summary: BMP4 promotes cardiomyocyte differentiation in a developmental context. Reason: PMID:20702560 reports BMP4-induced myofibrillar gene expression and cardiomyocyte contraction in chick anterior-heart-field progenitors, with FGF-pathway antagonism. Retain the cardiac differentiation/fiber-development outcomes as non-core without implying that BMP4 is a sarcomere component. |
| GO:0060391 positive regulation of SMAD protein signal transduction | IDA PMID:16816361 Bone morphogenetic protein-4 inhibitor gremlin is overexpres... | ACCEPT | Summary: BMP4 initiates SMAD signaling opposed by gremlin. Reason: PMID:16816361 studies responsiveness to exogenous and endogenous BMP4 in gremlin-rich lung fibroblast systems. The SMAD-pathway activation assignment agrees with direct BMP4 receptor biology; the kinase activity belongs to the receptors. |
| GO:0060391 positive regulation of SMAD protein signal transduction | IDA PMID:17244894 Antagonistic effects of bone morphogenetic protein-4 and -7 ... | ACCEPT | Summary: BMP4 activates SMAD signaling in mesangial cells. Reason: PMID:17244894 reports BMP4/SMAD-mediated modulation of aldosterone-induced responses. Retain the proximal signaling role while keeping its downstream antiproliferative consequence context dependent. |
| GO:0060391 positive regulation of SMAD protein signal transduction | IDA PMID:18787191 BMPER is an endothelial cell regulator and controls bone mor... | ACCEPT | Summary: BMP4 stimulates endothelial SMAD1/5 activation with BMPER. Reason: PMID:18787191 directly reports BMP4-dependent SMAD1/5 activation that requires BMPER in the tested endothelial system. This is a proximal output of the core ligand activity, not a BMP4 kinase reaction. |
| GO:0060391 positive regulation of SMAD protein signal transduction | IDA PMID:20559569 Endogenous Wnt/beta-catenin signaling is required for cardia... | ACCEPT | Summary: BMP4 stimulates SMAD signaling in human embryonic stem-cell experiments. Reason: PMID:20559569 examines BMP4/Wnt cross-regulation during human embryonic-stem-cell differentiation and documents BMP/SMAD signaling. Retain the proximal pathway activation, while not assigning BMP4 the intracellular Wnt or transcriptional machinery. Supporting Evidence: PMID:20559569 Treatment with BMP4 increased phosphorylation of Smad1 |
| GO:0060391 positive regulation of SMAD protein signal transduction | IDA PMID:9389648 Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-indu... | ACCEPT | Summary: BMP4 drives receptor-regulated SMAD responses. Reason: Selected PMID:9389648 experiments combine BMP4 stimulation with SMAD constructs and reporter assays; some nuclear-localization experiments also use activated receptor cotransfection. Retain the pathway activation with those assay limits and keep direct phosphorylation/DNA-binding activities on the receptors and SMADs. Supporting Evidence: PMID:9389648 enabled FlagβSmad4 to accumulate in the nucleus in response to BMP4 |
| GO:0060391 positive regulation of SMAD protein signal transduction | IEA GO_REF:0000117 | ACCEPT | Summary: Positive SMAD signaling is a characteristic BMP4 ligand response. Reason: The electronic assignment is independently corroborated by ligand-stimulated SMAD phosphorylation and signaling in PMIDs:14749725, 18787191 and 17992660. This proximal pathway output belongs in the core signaling synthesis without asserting intrinsic kinase activity. |
| GO:0060391 positive regulation of SMAD protein signal transduction | IMP PMID:17992660 Regulation of bone morphogenetic protein signalling in human... | ACCEPT | Summary: BMP4 activates endothelial SMAD signaling. Reason: PMID:17992660 reports BMP4-induced SMAD phosphorylation alongside endothelial proliferation and migration. This supports a proximal receptor-ligand signaling function distinct from the downstream vascular phenotype. |
| GO:0060425 lung morphogenesis | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | KEEP AS NON CORE | Summary: BMP4 contributes to embryonic lung morphogenesis. Reason: PMID:8674409 shows spatially patterned expression and substantial lung abnormalities after targeted mouse Bmp4 misexpression. Retain the developmental role with the perturbation context explicit; abnormal overexpression is not a measure of the normal direction of every branch-growth effect. |
| GO:0060426 lung vasculature development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 contributes to pulmonary vascular development and endothelial responses. Reason: PMID:17992660 combines Bmp4-deficient mouse lung vascular observations with endothelial BMP4 stimulation. Retain lung vasculature development as a tissue-specific outcome rather than a separate core molecular activity. |
| GO:0060426 lung vasculature development | IMP PMID:17992660 Regulation of bone morphogenetic protein signalling in human... | KEEP AS NON CORE | Summary: BMP4 contributes to pulmonary vascular development and endothelial responses. Reason: PMID:17992660 combines Bmp4-deficient mouse lung vascular observations with endothelial BMP4 stimulation. Retain lung vasculature development as a tissue-specific outcome rather than a separate core molecular activity. |
| GO:0060433 bronchus development | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | UNDECIDED | Summary: The precise bronchial or tracheal developmental assay remains unverified. Reason: PMID:8674409 supports lung morphogenesis, but its accessible abstract does not separately establish each named proximal-airway structure. Normal Clara-cell differentiation and distal-bud abnormalities do not by themselves resolve this exact bronchus/trachea annotation. |
| GO:0060438 trachea development | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | UNDECIDED | Summary: The precise bronchial or tracheal developmental assay remains unverified. Reason: PMID:8674409 supports lung morphogenesis, but its accessible abstract does not separately establish each named proximal-airway structure. Normal Clara-cell differentiation and distal-bud abnormalities do not by themselves resolve this exact bronchus/trachea annotation. |
| GO:0060441 epithelial tube branching involved in lung morphogenesis | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | KEEP AS NON CORE | Summary: BMP4 regulates the branching morphology of developing lung epithelium. Reason: PMID:8674409 directly reports altered terminal-bud architecture after Bmp4 misexpression in mouse lung. This supports involvement in branching morphogenesis, while the perturbation does not prescribe a uniform positive or negative effect under all developmental conditions. |
| GO:0060441 epithelial tube branching involved in lung morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 regulates the branching morphology of developing lung epithelium. Reason: PMID:8674409 directly reports altered terminal-bud architecture after Bmp4 misexpression in mouse lung. This supports involvement in branching morphogenesis, while the perturbation does not prescribe a uniform positive or negative effect under all developmental conditions. |
| GO:0060502 epithelial cell proliferation involved in lung morphogenesis | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | KEEP AS NON CORE | Summary: BMP4 influences epithelial proliferation during lung development. Reason: PMID:8674409 reports reduced BrdU labeling in embryonic lung epithelium after targeted Bmp4 misexpression. The source term specifies the developmental proliferation process without a positive direction; retain the observed inhibitory context. |
| GO:0060503 bud dilation involved in lung branching | IDA PMID:8674409 Evidence from normal expression and targeted misexpression t... | UNDECIDED | Summary: Pathological bud distension does not establish the normal bud-dilation role. Reason: PMID:8674409 reports grossly distended terminal buds after Bmp4 misexpression. The full experiment and term-specific physiological interpretation were not inspected sufficiently to decide whether this directly establishes normal bud dilation involved in branching. |
| GO:0060537 muscle tissue development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 regulates muscle-lineage development through extracellular signaling. Reason: BMP4 influences myoblast differentiation, cardiac progenitor differentiation and periureteral smooth-muscle development in distinct studies. The broad electronic process is compatible with these results but remains a pleiotropic developmental outcome, not a structural muscle function. |
| GO:0060976 coronary vasculature development | IEA GO_REF:0000107 | UNDECIDED | Summary: Coronary-specific donor evidence remains unverified. Reason: General heart morphogenesis or pulmonary angiogenesis does not independently establish coronary vasculature development. The precise mouse donor study was not inspected; preserve the transfer without extrapolating from another vascular bed. |
| GO:0060976 coronary vasculature development | ISS GO_REF:0000024 | UNDECIDED | Summary: Coronary-specific donor evidence remains unverified. Reason: General heart morphogenesis or pulmonary angiogenesis does not independently establish coronary vasculature development. The precise mouse donor study was not inspected; preserve the transfer without extrapolating from another vascular bed. |
| GO:0061036 positive regulation of cartilage development | IDA PMID:3201241 Novel regulators of bone formation: molecular clones and act... | UNDECIDED | Summary: The BMP4-specific cartilage experiment is not exposed by this source abstract. Reason: PMID:3201241 names BMP1, BMP2A and BMP3 in its accessible abstract. That is not evidence that the full paper lacks BMP4-related material. The relevant experiment remains inaccessible, so preserve the IDA row without a wrong-gene claim. |
| GO:0061036 positive regulation of cartilage development | IEA GO_REF:0000117 | UNDECIDED | Summary: A BMP4-specific cartilage-development basis for this prediction remains unresolved. Reason: BMP4 osteogenic activity is established, but the directly inspected SCUBE3 cartilage assays concern BMP2, and the BMP4-specific evidence behind PMID:3201241 is inaccessible. Retain this ARBA prediction pending a cartilage-specific source rather than importing a paralog result. |
| GO:0061047 positive regulation of branching involved in lung morphogenesis | IEA GO_REF:0000107 | UNDECIDED | Summary: The positive direction of lung-branching regulation needs the exact donor context. Reason: The mouse-transfer assertions may describe a context different from the inhibitory or distended-bud misexpression phenotype in PMID:8674409. The precise donor experiment was not inspected, so neither universal positive regulation nor refutation is justified. |
| GO:0061047 positive regulation of branching involved in lung morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: The positive direction of lung-branching regulation needs the exact donor context. Reason: The mouse-transfer assertions may describe a context different from the inhibitory or distended-bud misexpression phenotype in PMID:8674409. The precise donor experiment was not inspected, so neither universal positive regulation nor refutation is justified. |
| GO:0061626 pharyngeal arch artery morphogenesis | IEA GO_REF:0000107 | UNDECIDED | Summary: The pharyngeal-arch-artery donor experiment remains unverified. Reason: BMP4's broad cardiac developmental role does not by itself establish this specific artery-morphogenesis endpoint. Preserve the mouse transfer while seeking the original tissue- and stage-specific experiment. |
| GO:0061626 pharyngeal arch artery morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: The pharyngeal-arch-artery donor experiment remains unverified. Reason: BMP4's broad cardiac developmental role does not by itself establish this specific artery-morphogenesis endpoint. Preserve the mouse transfer while seeking the original tissue- and stage-specific experiment. |
| GO:0070244 negative regulation of thymocyte apoptotic process | IMP PMID:12421925 Bone morphogenetic protein 2/4 signaling regulates early thy... | KEEP AS NON CORE | Summary: BMP4 supports thymocyte survival in the source study. Reason: PMID:12421925 reports enhanced survival alongside inhibited thymocyte proliferation and differentiation. Retain negative regulation of thymocyte apoptosis as a non-core context-dependent effect; reduced expansion is not interpreted as increased death. |
| GO:0070700 BMP receptor binding | IDA PMID:7811286 A mammalian serine/threonine kinase receptor specifically bi... | ACCEPT | Summary: BMP receptor binding is intrinsic to BMP4 ligand function. Reason: PMID:7811286 directly characterizes a mammalian serine/threonine kinase receptor binding BMP4, and PMID:12045205 measures radiolabeled BMP4 binding to BMPR2 constructs. These support the direct and electronic receptor-binding assignments as core ligand properties. Supporting Evidence: PMID:7811286 specifically binds BMP-2 and BMP-4 |
| GO:0070700 BMP receptor binding | IEA GO_REF:0000117 | ACCEPT | Summary: BMP receptor binding is intrinsic to BMP4 ligand function. Reason: PMID:7811286 directly characterizes a mammalian serine/threonine kinase receptor binding BMP4, and PMID:12045205 measures radiolabeled BMP4 binding to BMPR2 constructs. These support the direct and electronic receptor-binding assignments as core ligand properties. |
| GO:0071773 cellular response to BMP stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 participates upstream in receptor-dependent cellular BMP responses. Reason: PMID:18326817 identifies endogenous BMP4 in the HJV-dependent receptor system. Retain the cellular-response annotation as a broad downstream signaling context, while keeping the extracellular ligand distinct from the responding cell's receptor kinases and transcription factors. |
| GO:0071773 cellular response to BMP stimulus | IMP PMID:18326817 Hemojuvelin regulates hepcidin expression via a selective su... | KEEP AS NON CORE | Summary: BMP4 participates upstream in receptor-dependent cellular BMP responses. Reason: PMID:18326817 identifies endogenous BMP4 in the HJV-dependent receptor system. Retain the cellular-response annotation as a broad downstream signaling context, while keeping the extracellular ligand distinct from the responding cell's receptor kinases and transcription factors. |
| GO:0072104 glomerular capillary formation | IEA GO_REF:0000107 | UNDECIDED | Summary: The glomerular-capillary donor experiment remains unverified. Reason: Kidney development and effects on nephrogenesis are relevant but do not specifically establish glomerular capillary formation. The original mouse donor experiment and vascular endpoint were not inspected. |
| GO:0072104 glomerular capillary formation | ISS GO_REF:0000024 | UNDECIDED | Summary: The glomerular-capillary donor experiment remains unverified. Reason: Kidney development and effects on nephrogenesis are relevant but do not specifically establish glomerular capillary formation. The original mouse donor experiment and vascular endpoint were not inspected. |
| GO:0072125 negative regulation of glomerular mesangial cell proliferation | IDA PMID:17244894 Antagonistic effects of bone morphogenetic protein-4 and -7 ... | KEEP AS NON CORE | Summary: BMP4 inhibits stimulated mesangial cell proliferation. Reason: PMID:17244894 directly describes suppression of aldosterone-induced mesangial mitosis by BMP4 signaling. Retain the negative proliferative response in that renal cell and stimulation context. |
| GO:0072179 nephric duct formation | IDA PMID:10021330 The surface ectoderm is essential for nephric duct formation... | KEEP AS NON CORE | Summary: BMP4 provides an inductive signal for nephric-duct formation. Reason: PMID:10021330 reports BMP4-bead rescue of nephric-duct differentiation after removal of surface ectoderm. This supports a developmental signaling role without assigning BMP4 a structural component function in the duct. |
| GO:0072197 ureter morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 contributes to ureter morphogenesis. Reason: PMID:12631064 reports Bmp4-dependent periureteral mesenchymal organization, alpha-SMA-positive cells and local chemotaxis. This corroborates the mouse-derived morphogenesis assignment as a context-specific use of BMP4 signaling. |
| GO:0072200 negative regulation of mesenchymal cell proliferation involved in ureter development | IDA PMID:12399320 Sonic hedgehog regulates proliferation and differentiation o... | UNDECIDED | Summary: The exact negative mesenchymal proliferation assay requires inspection. Reason: PMID:12399320 places BMP4 downstream of SHH but states that it does not mediate SHH's proliferative effect. This is not equivalent to either proving or refuting a separate BMP4 inhibitory assay. The source assertion remains undecided pending the direct experiment. |
| GO:0090189 regulation of branching involved in ureteric bud morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 can inhibit ureteric branching in metanephric explants. Reason: PMID:12141440 directly tests BMP4 and reports inhibition of branching in mouse metanephric cultures at the tested concentrations. This supports negative and broader regulatory annotations, with dose and explant context retained rather than assuming BMP4 has one direction of effect in every developmental setting. |
| GO:0090191 negative regulation of branching involved in ureteric bud morphogenesis | IDA PMID:12141440 BMPs and BMP receptors in mouse metanephric development: in ... | KEEP AS NON CORE | Summary: BMP4 can inhibit ureteric branching in metanephric explants. Reason: PMID:12141440 directly tests BMP4 and reports inhibition of branching in mouse metanephric cultures at the tested concentrations. This supports negative and broader regulatory annotations, with dose and explant context retained rather than assuming BMP4 has one direction of effect in every developmental setting. |
| GO:0090191 negative regulation of branching involved in ureteric bud morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 can inhibit ureteric branching in metanephric explants. Reason: PMID:12141440 directly tests BMP4 and reports inhibition of branching in mouse metanephric cultures at the tested concentrations. This supports negative and broader regulatory annotations, with dose and explant context retained rather than assuming BMP4 has one direction of effect in every developmental setting. |
| GO:0090194 negative regulation of glomerulus development | IDA PMID:12141440 BMPs and BMP receptors in mouse metanephric development: in ... | KEEP AS NON CORE | Summary: BMP4 can suppress nephrogenesis in the source explant assay. Reason: PMID:12141440 reports reduced nephrogenesis following BMP4 treatment of mouse metanephric explants. Retain the curated glomerular-development regulatory assignment as a non-core culture phenotype, without implying that endogenous BMP4 invariably prevents kidney formation. |
| GO:1900182 positive regulation of protein localization to nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BMP4 signaling promotes nuclear accumulation of downstream proteins. Reason: Selected PMID:9389648 Results show BMP4-associated nuclear redistribution of SMAD constructs, and PMID:22529382 discusses TEAD4 localization after BMP4 treatment. These corroborate the broad mouse-transfer localization effect without resolving import versus export/retention or assigning transport activity to BMP4. |
| GO:1900745 positive regulation of p38MAPK cascade | IDA PMID:17600318 BMP4 induces HO-1 via a Smad-independent, p38MAPK-dependent ... | KEEP AS NON CORE | Summary: BMP4 can activate the p38 MAPK pathway in pulmonary artery smooth-muscle cells. Reason: PMID:17600318 connects BMP4-induced HO-1 expression and growth inhibition to p38 MAPK/ERK signaling. Retain the source and corroborated electronic p38-cascade assignments as a noncanonical context-dependent response, not BMP4 kinase activity. |
| GO:1900745 positive regulation of p38MAPK cascade | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 can activate the p38 MAPK pathway in pulmonary artery smooth-muscle cells. Reason: PMID:17600318 connects BMP4-induced HO-1 expression and growth inhibition to p38 MAPK/ERK signaling. Retain the source and corroborated electronic p38-cascade assignments as a noncanonical context-dependent response, not BMP4 kinase activity. |
| GO:1901331 positive regulation of odontoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BMP4 supports odontoblast-associated differentiation during tooth development. Reason: PMID:11023873 reports rescue of Msx1-deficient tooth germs through definitive dentin formation after BMP4 exposure and grafting. This corroborates the ortholog-derived developmental differentiation capacity, while the precise original donor edge was not reconstructed and mature odontoblast survival is not equated with differentiation. |
| GO:1901331 positive regulation of odontoblast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BMP4 supports odontoblast-associated differentiation during tooth development. Reason: PMID:11023873 reports rescue of Msx1-deficient tooth germs through definitive dentin formation after BMP4 exposure and grafting. This corroborates the ortholog-derived developmental differentiation capacity, while the precise original donor edge was not reconstructed and mature odontoblast survival is not equated with differentiation. |
| GO:1902893 regulation of miRNA transcription | IMP NOT PMID:18548003 SMAD proteins control DROSHA-mediated microRNA maturation. | KEEP AS NON CORE | Summary: The transcriptional NOT result is specific to the tested miR-21 response. Reason: Selected PMID:18548003 Results distinguish BMP4-induced pri-miR-21 processing from transcription using time courses, alpha-amanitin, promoter reporters and CMV-driven pri-miR-21. Preserve the NOT flag in that target/cell context, not as a universal inability to regulate miRNA transcription. PMID:22988237 reports a separate BMP4 effect on miR-302β367 transcription. |
| GO:1902894 negative regulation of miRNA transcription | IDA PMID:28124060 Bone morphogenetic protein 4 regulates microRNAs miR-494 and... | UNDECIDED | Summary: Reduced miR-494 abundance does not resolve a transcription-specific mechanism. Reason: PMID:28124060 reports decreased miR-494 expression in BMP4-stimulated endothelial cells, but the accessible abstract does not distinguish transcription from processing or stability. The exact transcription assay behind this IDA assertion remains unverified. |
| GO:1904706 negative regulation of vascular associated smooth muscle cell proliferation | TAS PMID:22988237 Inhibition of microRNA-302 (miR-302) by bone morphogenetic p... | UNDECIDED | Summary: The specific vascular smooth-muscle proliferation or migration experiment is not accessible. Reason: PMID:22988237 directly supports the BMP4βmiR-302βBMPRII feedback mechanism in its abstract, but the corresponding cell-proliferation/migration experiment behind these TAS assertions was not inspected. Retain each source endpoint without deriving it automatically from receptor-expression changes. |
| GO:1904753 negative regulation of vascular associated smooth muscle cell migration | TAS PMID:22988237 Inhibition of microRNA-302 (miR-302) by bone morphogenetic p... | UNDECIDED | Summary: The specific vascular smooth-muscle proliferation or migration experiment is not accessible. Reason: PMID:22988237 directly supports the BMP4βmiR-302βBMPRII feedback mechanism in its abstract, but the corresponding cell-proliferation/migration experiment behind these TAS assertions was not inspected. Retain each source endpoint without deriving it automatically from receptor-expression changes. |
| GO:1905072 cardiac jelly development | ISS NOT GO_REF:0000024 | KEEP AS NON CORE | Summary: The cardiac-jelly NOT assertion is supported for initial jelly formation in the conditional anterior-heart-field model. Reason: PMID:18924235 detected alcian-blue-stained cardiac jelly in both control and Mef2c-AHF-Cre conditional Bmp4 knockout embryonic hearts at E10.5. This acidic-glycosaminoglycan stain supports retained initial jelly formation despite loss of BMP4 from anterior-heart-field-derived myocardium. Keep the mouse-derived NOT transfer as non-core within this tissue, stage and staining endpoint; it does not establish that every jelly component, later remodeling or BMP4 source is dispensable. Supporting Evidence: |
| GO:1905312 positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis | IEA GO_REF:0000107 | UNDECIDED | Summary: The precise cardiac neural-crest migration donor experiment remains unverified. Reason: The mouse electronic transfer specifies both neural-crest migration and outflow-tract context. General cardiac phenotypes and neural-crest dependence of cardiomyocyte differentiation do not independently establish that exact migration result. |
| GO:2000005 negative regulation of metanephric S-shaped body morphogenesis | IDA PMID:12141440 BMPs and BMP receptors in mouse metanephric development: in ... | UNDECIDED | Summary: The exact nephron-body stage underlying this inhibition is not exposed by the abstract. Reason: PMID:12141440 reports reduced nephrogenesis in BMP4-treated metanephric explants, but the inspected abstract does not distinguish S-shaped from comma-shaped body morphogenesis. Preserve each source assertion pending the stage-specific source data. |
| GO:2000007 negative regulation of metanephric comma-shaped body morphogenesis | IDA PMID:12141440 BMPs and BMP receptors in mouse metanephric development: in ... | UNDECIDED | Summary: The exact nephron-body stage underlying this inhibition is not exposed by the abstract. Reason: PMID:12141440 reports reduced nephrogenesis in BMP4-treated metanephric explants, but the inspected abstract does not distinguish S-shaped from comma-shaped body morphogenesis. Preserve each source assertion pending the stage-specific source data. |
| GO:2000636 positive regulation of primary miRNA processing | IDA PMID:18548003 SMAD proteins control DROSHA-mediated microRNA maturation. | KEEP AS NON CORE | Summary: BMP4 promotes primary-miRNA processing through downstream SMAD/DROSHA machinery. Reason: Selected PMID:18548003 Results show enhanced pre/mature miR-21, SMAD1/5/p68 dependence and increased pri-to-pre processing in nuclear extracts after BMP4 stimulation. BMP4 is the extracellular trigger; DROSHA and its partners perform RNA processing. Retain the target and cell-context limits. |
| GO:2000725 regulation of cardiac muscle cell differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BMP4 regulates cardiac muscle differentiation through a progenitor signaling program. Reason: PMID:20702560 reports BMP4-induced cardiomyocyte differentiation through FGF-pathway antagonism in chick anterior-heart-field tissue. This corroborates the ARBA regulatory assignment as a developmental outcome rather than a separate core molecular activity. |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | UNDECIDED | Summary: The extrinsic apoptotic-pathway mechanism needs specific donor evidence. Reason: BMP4 can promote survival in thymic and renal systems, but that does not identify an extrinsic death-receptor mechanism. The exact mouse donor experiment for this mechanistic term was not inspected; preserve the assertions without overgeneralizing the survival phenotype. |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | ISS GO_REF:0000024 | UNDECIDED | Summary: The extrinsic apoptotic-pathway mechanism needs specific donor evidence. Reason: BMP4 can promote survival in thymic and renal systems, but that does not identify an extrinsic death-receptor mechanism. The exact mouse donor experiment for this mechanistic term was not inspected; preserve the assertions without overgeneralizing the survival phenotype. |
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Download this section (compressed HTML)Q: Which exact mouse experiments and developmental contexts support each of the five cardiac NOT transfers, and do their GO evidence edges identify the conditional models inspected here?
Q: Which DAF-4 construct in PMID:8413626 maps to each of G8JY02, P50488 and Q8ITX8 in the three BMP4 binding assertions?
Q: Which condition or intervention supports positive smooth-muscle proliferation in PMID:17600318, whose accessible abstract emphasizes BMP4/HO-1-mediated growth inhibition?
Q: Does BMP4 change TEAD4 nuclear import directly in PMID:22529382, or do export, retention or protein abundance explain the localization response?
Q: How do BMP4 prodomain binding to fibrillin fragments and mature-ligand responses depend on tissue matrix composition and processing state?
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