id: MODULE:bmp_signaling title: BMP signaling pathway module description: BMP ligands activate type I and type II serine/threonine kinase receptor complexes that phosphorylate SMAD1/5-family effectors and regulate developmental patterning and differentiation. status: DRAFT evidence: - source_id: file:modules/bmp_signaling-deep-research-falcon.md title: BMP signaling pathway Falcon module review statement: >- Falcon/Edison module review generated 2026-06-28 is linked as supporting evidence for module boundaries, core mechanism, variation, constraints, and failure modes; open questions in that report require manual review before promotion to curated knowledge gaps. - source_id: GO:0030509 title: BMP signaling pathway statement: The module is grounded in the GO biological process term for BMP signaling pathway. - source_id: PANTHER:PTN000218063 title: PAINT node PTN000218063 for BMP4 statement: Local PAINT IBD node in PTHR11848 with propagated terms C:GO:0005576, F:GO:0005125, P:GO:0007178; PAINT date 20260528. - source_id: PANTHER:PTN002626129 title: PAINT node PTN002626129 for BMP4 statement: Local PAINT IBD node in PTHR11848 with propagated terms P:GO:0008284; PAINT date 20250415. - source_id: PANTHER:PTN008330973 title: PAINT node PTN008330973 for BMP4 statement: Local PAINT IBD node in PTHR11848 with propagated terms P:GO:0003007; PAINT date 20250403. - source_id: PANTHER:PTN008983382 title: PAINT node PTN008983382 for BMP4 statement: Local PAINT IBD node in PTHR11848 with propagated terms P:GO:0030509; PAINT date 20250403. notes: >- Curated compact signaling-pathway module generated from verified UniProt exemplar accessions and local PAINT IBD rows. PTN anchors are included only when the exemplar accession appears in an IBD seed row in interpro/panther; roles without local PAINT seeds remain grounded by verified UniProt exemplar accessions. Nuclear entry step (2026-11-05): added R-SMAD/SMAD4 complex formation and SMAD nuclear import (by module_ref to karyopherin_nuclear_protein_import), so that the module states the steps GO-CAM BMP models compress into a receptor -> nuclear SMAD edge; GO-CAM activities realizing the receptor and SMAD steps are pinned with gocam_associations. Falcon integration (2026-06-28): Falcon findings are linked as evidence and family-level support. Automatically extracted open-question headings were intentionally not retained as knowledge_gap entries because they were not manually curated. Machine-generated Falcon citations remain curation support and are not manually adjudicated here. module: id: bmp_signaling label: BMP signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: BMP signaling pathway term: id: GO:0030509 label: BMP signaling pathway description: BMP ligands activate type I and type II serine/threonine kinase receptor complexes that phosphorylate SMAD1/5-family effectors and regulate developmental patterning and differentiation. context: taxa: - preferred_term: metazoa term: id: NCBITaxon:33208 label: Metazoa cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: bmp receptor engagement node: id: bmp_receptor_engagement label: BMP receptor engagement gocam_associations: - model: gomodel:645d887900000999 activity: gomodel:645d887900000999/66e382fb00001905 title: BMP7 signaling leading to osteoblast differentiation (Human) notes: ACVR1 activity in this model. - model: gomodel:66e382fb00001606 activity: gomodel:66e382fb00001606/66e382fb00001707 title: Hepcidin induction by BMP6 signaling (Human) notes: ACVR1 activity in this model. module_type: REGULATORY_STEP description: BMP4 ligand engages BMPR type I and type II receptor chains. annotons: - id: bmp4_bmp4_ligand label: BMP4 ligand participant: selector_type: FAMILY family: preferred_term: BMP4 ligand family/ortholog group term: id: PANTHER:PTHR11848 label: TGF-BETA FAMILY representative_members: - preferred_term: BMP4 term: id: UniProtKB:P12644 label: Bone morphogenetic protein 4 (BMP-4) (Bone morphogenetic protein 2B) (BMP-2B) ancestral_nodes: - preferred_term: PAINT node PTN000218063 for BMP4 term: id: PANTHER:PTN000218063 label: PTN000218063 description: Local PAINT IBD node in PTHR11848 with propagated terms C:GO:0005576, F:GO:0005125, P:GO:0007178; PAINT date 20260528. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000218063 in PTHR11848. - preferred_term: PAINT node PTN002626129 for BMP4 term: id: PANTHER:PTN002626129 label: PTN002626129 description: Local PAINT IBD node in PTHR11848 with propagated terms P:GO:0008284; PAINT date 20250415. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002626129 in PTHR11848. - preferred_term: PAINT node PTN008330973 for BMP4 term: id: PANTHER:PTN008330973 label: PTN008330973 description: Local PAINT IBD node in PTHR11848 with propagated terms P:GO:0003007; PAINT date 20250403. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008330973 in PTHR11848. - preferred_term: PAINT node PTN008983382 for BMP4 term: id: PANTHER:PTN008983382 label: PTN008983382 description: Local PAINT IBD node in PTHR11848 with propagated terms P:GO:0030509; PAINT date 20250403. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008983382 in PTHR11848. evidence: - source_id: file:interpro/panther/PTHR11848/PTHR11848-deep-research-falcon.md title: PTHR11848 Falcon family review statement: >- Falcon family-level GO review: PTHR11848 is a broad TGF-beta superfamily parent whose empty InterPro2GO mapping is treated as sound because no single GO term is safely true for all ligands, antagonists, and divergent members. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the bmp4 ligand role in BMP signaling pathway. - id: bmpr1a_bmpr1a_type_i_receptor label: BMPR1A type I receptor gocam_associations: - model: gomodel:645d887900001795 activity: gomodel:645d887900001795/645d887900001803 title: BMP2 signaling pathway (Human) notes: BMPR1A activity in this model. - model: gomodel:66e382fb00001232 activity: gomodel:66e382fb00001232/66e382fb00001247 title: BMP4 signaling pathway (Human) notes: BMPR1A activity in this model. - model: gomodel:66e382fb00001388 activity: gomodel:66e382fb00001388/66e382fb00001403 title: BMP5 role in dendritic growth via SMAD1 (Human) notes: BMPR1A activity in this model. - model: gomodel:66e382fb00001786 activity: gomodel:66e382fb00001786/66e382fb00001885 title: Hepcidin induction by BMP2/BMP6 complex signaling (Human) notes: BMPR1A activity in this model. - model: gomodel:66e382fb00002105 activity: gomodel:66e382fb00002105/66e382fb00002169 title: BMP8A role in spermatogenesis via SMAD1, SMAD5 and SMAD9 (Human) notes: BMPR1A activity in this model. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: BMPR1A term: id: UniProtKB:P36894 label: Bone morphogenetic protein receptor type-1A (BMP type-1A receptor) (BMPR-1A) (EC 2.7.11.30) (Activin receptor-like kinase 3) (ALK-3) (Serine/threonine-protein kinase receptor R5) (SKR5) (CD antigen CD292) role_description: Curated exemplar for the bmpr1a type i receptor role in BMP signaling pathway. - id: bmpr2_bmpr2_type_ii_receptor label: BMPR2 type II receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: BMPR2 term: id: UniProtKB:Q13873 label: Bone morphogenetic protein receptor type-2 (BMP type-2 receptor) (BMPR-2) (EC 2.7.11.30) (Bone morphogenetic protein receptor type II) (BMP type II receptor) (BMPR-II) role_description: Curated exemplar for the bmpr2 type ii receptor role in BMP signaling pathway. - order: 2 role: receptor smad phosphorylation node: id: smad1_5_activation label: SMAD1/5 activation module_type: REGULATORY_STEP description: BMP receptors phosphorylate receptor-regulated SMAD1 and SMAD5. annotons: - id: smad1_smad1_receptor_regulated_smad label: SMAD1 receptor-regulated SMAD participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SMAD1 term: id: UniProtKB:Q15797 label: SMAD family member 1 (SMAD 1) (hSMAD1) (JV4-1) (Mad-related protein 1) (Mothers against decapentaplegic homolog 1) (MAD homolog 1) (Mothers against DPP homolog 1) (Transforming growth factor-beta-signaling protein 1) (BSP-1) role_description: Curated exemplar for the smad1 receptor-regulated smad role in BMP signaling pathway. - id: smad5_smad5_receptor_regulated_smad label: SMAD5 receptor-regulated SMAD participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SMAD5 term: id: UniProtKB:Q99717 label: SMAD family member 5 (SMAD 5) (hSmad5) (JV5-1) (Mothers against decapentaplegic homolog 5) (MAD homolog 5) (Mothers against DPP homolog 5) role_description: Curated exemplar for the smad5 receptor-regulated smad role in BMP signaling pathway. - order: 3 role: R-SMAD/SMAD4 complex formation and nuclear import node: id: smad_complex_nuclear_import label: R-SMAD/SMAD4 complex formation and nuclear import module_type: TRANSPORT_STEP description: >- Receptor-phosphorylated SMAD1/5/9 leave the receptor, bind the common mediator SMAD4, and accumulate in the nucleus. GO-CAM models compress this into a single edge from a plasma-membrane type I receptor kinase to a nuclear SMAD transcription factor activity (see projects/GOCAM_COMPARTMENTS.md). Two other gene products are needed: SMAD4, a pathway-specific partner, and the import machinery (importin-7/8 and importin-beta1 with the Ran system), included here by reference. parts: - order: 1 role: R-SMAD/SMAD4 complex formation node: id: r_smad_smad4_complex label: R-SMAD/SMAD4 complex formation module_type: REGULATORY_STEP description: >- Phosphorylated SMAD1/5/9 bind SMAD4 in response to BMP. SMAD4 is required for BMP-SMAD transcriptional responses. annotons: - id: smad4_complex_partner label: SMAD4 partner of phospho-SMAD1/5/9 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SMAD4 term: id: UniProtKB:Q13485 label: SMAD family member 4 function: preferred_term: R-SMAD binding term: id: GO:0070412 label: R-SMAD binding processes: - preferred_term: SMAD protein signal transduction term: id: GO:0060395 label: SMAD protein signal transduction locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Binds receptor-phosphorylated SMAD1/5/9 to form the heteromeric complex that enters the nucleus. evidence: - source_id: PMID:8893010 title: Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. statement: SMAD4 (DPC4) associates with SMAD1 in response to BMP and is essential for SMAD1 function. supporting_text: >- DPC4 associates with Smad1 in response to BMP - source_id: PMID:11509558 title: Nucleocytoplasmic shuttling of Smad1 conferred by its nuclear localization and nuclear export signals. statement: BMP triggers SMAD1 phosphorylation, SMAD4 binding and nuclear accumulation. supporting_text: >- BMP addition triggers Smad1 serine phosphorylation, binding of Smad4, and its accumulation in the nucleus. - order: 2 role: SMAD nuclear import node: id: smad_nuclear_import label: SMAD nuclear import module_type: TRANSPORT_STEP description: >- Activated SMAD complexes are carried into the nucleus directly by importin-beta-family carriers (importin-7 and importin-8; the SMAD MH1 basic motif is required), without an importin-alpha adaptor. module_ref: karyopherin_nuclear_protein_import evidence: - source_id: PMID:17785517 title: Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads. statement: Importin-7 and importin-8 are needed for nuclear accumulation of BMP-activated SMAD1. supporting_text: >- knockdown of importin 7 and 8 (Imp7 and 8), the mammalian orthologues of Msk, markedly impaired nuclear accumulation of Smad1 in response to BMP2 - source_id: PMID:11509558 title: Nucleocytoplasmic shuttling of Smad1 conferred by its nuclear localization and nuclear export signals. statement: The SMAD1 N-terminal basic NLS-like motif is required for ligand-induced nuclear translocation. supporting_text: >- Mutations in the Smad1 N-terminal basic nuclear localization signal (NLS)-like motif, conserved among all Smad proteins, eliminated its ligand-induced nuclear translocation connections: - source: r_smad_smad4_complex target: smad_nuclear_import connection_type: PRECEDES description: The phospho-SMAD/SMAD4 complex is the import cargo. - order: 4 role: bmp transcriptional output node: id: bmp_transcriptional_output label: BMP transcriptional output gocam_associations: - model: gomodel:645d887900000999 activity: gomodel:645d887900000999/66e382fb00002029 title: BMP7 signaling leading to osteoblast differentiation (Human) notes: SMAD9 activity in this model. - model: gomodel:645d887900001795 activity: gomodel:645d887900001795/646ff70100002384 title: BMP2 signaling pathway (Human) notes: SMAD5 activity in this model. - model: gomodel:645d887900001795 activity: gomodel:645d887900001795/646ff70100002392 title: BMP2 signaling pathway (Human) notes: SMAD9 activity in this model. - model: gomodel:66e382fb00001232 activity: gomodel:66e382fb00001232/66e382fb00001273 title: BMP4 signaling pathway (Human) notes: SMAD5 activity in this model. - model: gomodel:66e382fb00001232 activity: gomodel:66e382fb00001232/66e382fb00001281 title: BMP4 signaling pathway (Human) notes: SMAD9 activity in this model. - model: gomodel:66e382fb00001606 activity: gomodel:66e382fb00001606/66e382fb00001719 title: Hepcidin induction by BMP6 signaling (Human) notes: SMAD5 activity in this model. - model: gomodel:66e382fb00001606 activity: gomodel:66e382fb00001606/66e382fb00001724 title: Hepcidin induction by BMP6 signaling (Human) notes: SMAD9 activity in this model. - model: gomodel:66e382fb00001786 activity: gomodel:66e382fb00001786/66e382fb00001814 title: Hepcidin induction by BMP2/BMP6 complex signaling (Human) notes: SMAD5 activity in this model. - model: gomodel:66e382fb00001786 activity: gomodel:66e382fb00001786/66e382fb00001819 title: Hepcidin induction by BMP2/BMP6 complex signaling (Human) notes: SMAD9 activity in this model. - model: gomodel:66e382fb00002105 activity: gomodel:66e382fb00002105/66e382fb00002197 title: BMP8A role in spermatogenesis via SMAD1, SMAD5 and SMAD9 (Human) notes: SMAD5 activity in this model. - model: gomodel:66e382fb00002105 activity: gomodel:66e382fb00002105/66e382fb00002214 title: BMP8A role in spermatogenesis via SMAD1, SMAD5 and SMAD9 (Human) notes: SMAD9 activity in this model. module_type: REGULATORY_STEP description: SMAD4 complexes relay BMP receptor activation to nuclear transcriptional responses. annotons: - id: smad4_smad4_common_mediator label: SMAD4 common mediator participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SMAD4 term: id: UniProtKB:Q13485 label: SMAD family member 4 (SMAD 4) (hSMAD4) (Deletion target in pancreatic carcinoma 4) (Mothers against decapentaplegic homolog 4) (MAD homolog 4) (Mothers against DPP homolog 4) role_description: Curated exemplar for the smad4 common mediator role in BMP signaling pathway. - id: smad1_smad1_transcriptional_effector label: SMAD1 transcriptional effector gocam_associations: - model: gomodel:645d887900000999 activity: gomodel:645d887900000999/66e382fb00002012 title: BMP7 signaling leading to osteoblast differentiation (Human) notes: SMAD1 activity in this model. - model: gomodel:645d887900001795 activity: gomodel:645d887900001795/646ff70100002376 title: BMP2 signaling pathway (Human) notes: SMAD1 activity in this model. - model: gomodel:66e382fb00001232 activity: gomodel:66e382fb00001232/66e382fb00001262 title: BMP4 signaling pathway (Human) notes: SMAD1 activity in this model. - model: gomodel:66e382fb00001388 activity: gomodel:66e382fb00001388/66e382fb00001396 title: BMP5 role in dendritic growth via SMAD1 (Human) notes: SMAD1 activity in this model. - model: gomodel:66e382fb00001606 activity: gomodel:66e382fb00001606/66e382fb00001713 title: Hepcidin induction by BMP6 signaling (Human) notes: SMAD1 activity in this model. - model: gomodel:66e382fb00001786 activity: gomodel:66e382fb00001786/66e382fb00001808 title: Hepcidin induction by BMP2/BMP6 complex signaling (Human) notes: SMAD1 activity in this model. - model: gomodel:66e382fb00002105 activity: gomodel:66e382fb00002105/66e382fb00002185 title: BMP8A role in spermatogenesis via SMAD1, SMAD5 and SMAD9 (Human) notes: SMAD1 activity in this model. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SMAD1 term: id: UniProtKB:Q15797 label: SMAD family member 1 (SMAD 1) (hSMAD1) (JV4-1) (Mad-related protein 1) (Mothers against decapentaplegic homolog 1) (MAD homolog 1) (Mothers against DPP homolog 1) (Transforming growth factor-beta-signaling protein 1) (BSP-1) role_description: Curated exemplar for the smad1 transcriptional effector role in BMP signaling pathway. connections: - source: bmp_receptor_engagement target: smad1_5_activation connection_type: CAUSES description: The initiating event promotes receptor smad phosphorylation. - source: smad1_5_activation target: smad_complex_nuclear_import connection_type: PRECEDES description: Phosphorylated SMAD1/5 leave the receptor and bind SMAD4. - source: smad_complex_nuclear_import target: bmp_transcriptional_output connection_type: PROVIDES_INPUT_FOR description: Nuclear SMAD1/5-SMAD4 complexes regulate BMP target genes.