id: MODULE:nodal_signaling title: Nodal signaling pathway module description: Nodal/TGF-beta family ligands use EGF-CFC co-receptors and activin-class receptors to activate SMAD2/3 transcriptional programs for embryonic axis formation and cell-fate decisions. status: DRAFT evidence: - source_id: file:modules/nodal_signaling-deep-research-falcon.md title: Nodal 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:0038092 title: nodal signaling pathway statement: The module is grounded in the GO biological process term for nodal signaling pathway. - source_id: PANTHER:PTN000218063 title: PAINT node PTN000218063 for NODAL 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:PTN000746990 title: PAINT node PTN000746990 for NODAL statement: Local PAINT IBD node in PTHR11848 with propagated terms P:GO:0030154, P:GO:0038092; PAINT date 20250902. notes: >- Nuclear entry step (2026-11-10): SMAD2/3-SMAD4 nuclear import is now an explicit step, included by module_ref to karyopherin_nuclear_protein_import. No cached production GO-CAM models Nodal signaling, so no GO-CAM activities are pinned yet. 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. 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: nodal_signaling label: Nodal signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: nodal signaling pathway term: id: GO:0038092 label: nodal signaling pathway description: Nodal/TGF-beta family ligands use EGF-CFC co-receptors and activin-class receptors to activate SMAD2/3 transcriptional programs for embryonic axis formation and cell-fate decisions. 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: nodal coreceptor engagement node: id: nodal_coreceptor_engagement label: Nodal coreceptor engagement module_type: REGULATORY_STEP description: NODAL ligand and CRIPTO co-receptor promote activin receptor complex signaling. annotons: - id: nodal_nodal_ligand label: Nodal ligand participant: selector_type: FAMILY family: preferred_term: Nodal ligand family/ortholog group term: id: PANTHER:PTHR11848 label: TGF-BETA FAMILY representative_members: - preferred_term: NODAL term: id: UniProtKB:Q96S42 label: Nodal homolog ancestral_nodes: - preferred_term: PAINT node PTN000218063 for NODAL 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 PTN000746990 for NODAL term: id: PANTHER:PTN000746990 label: PTN000746990 description: Local PAINT IBD node in PTHR11848 with propagated terms P:GO:0030154, P:GO:0038092; PAINT date 20250902. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000746990 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 nodal ligand role in nodal signaling pathway. - id: cripto_cripto_co_receptor label: CRIPTO co-receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CRIPTO term: id: UniProtKB:P13385 label: Protein Cripto (Cripto, EGF-CFC family member) (Cripto-1 growth factor) (CRGF) (Epidermal growth factor-like cripto protein CR1) (Teratocarcinoma-derived growth factor 1) role_description: Curated exemplar for the cripto co-receptor role in nodal signaling pathway. - order: 2 role: nodal receptor activation node: id: nodal_receptor_activation label: Nodal receptor activation module_type: REGULATORY_STEP description: ACVR1B and ACVR2B receptor chains relay Nodal ligand input. annotons: - id: acvr1b_acvr1b_type_i_receptor label: ACVR1B type I receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ACVR1B term: id: UniProtKB:P36896 label: Activin receptor type-1B (EC 2.7.11.30) (Activin receptor type IB) (ACTR-IB) (Activin receptor-like kinase 4) (ALK-4) (Serine/threonine-protein kinase receptor R2) (SKR2) role_description: Curated exemplar for the acvr1b type i receptor role in nodal signaling pathway. - id: acvr2b_acvr2b_type_ii_receptor label: ACVR2B type II receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ACVR2B term: id: UniProtKB:Q13705 label: Activin receptor type-2B (EC 2.7.11.30) (Activin receptor type IIB) (ACTR-IIB) role_description: Curated exemplar for the acvr2b type ii receptor role in nodal signaling pathway. - order: 3 role: R-SMAD nuclear import node: id: nodal_smad_nuclear_import label: SMAD2/3-SMAD4 nuclear import module_type: TRANSPORT_STEP description: >- Receptor-phosphorylated SMAD2/3, with SMAD4, enter the nucleus through the karyopherin import cycle, included here by reference. Activated SMAD3 binds importin-beta1 directly through its N-terminal domain and is released by RanGTP; SMAD2 cannot bind importin-beta1 because of its exon-3 insert, and both depend on importin-7/8. This is the step that GO-CAM models compress into a single edge from the plasma-membrane type I receptor to a nuclear SMAD transcription factor activity (see projects/GOCAM_COMPARTMENTS.md). module_ref: karyopherin_nuclear_protein_import evidence: - source_id: PMID:11294908 title: Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner. statement: Receptor-activated SMAD3 binds importin-beta1 through its N-terminal domain; SMAD2 does not. supporting_text: >- Smad3, via its N-terminal domain, interacts specifically with importin-beta1 and only after activation by receptor. - 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 activated SMAD2/3; their fly orthologue Moleskin imports phosphorylated Mad. supporting_text: >- markedly impaired nuclear accumulation of Smad1 in response to BMP2 and of Smad2/3 in response to TGF-beta. - source_id: PMID:17785517 title: Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads. statement: Moleskin, the Drosophila importin-7 orthologue, is required for nuclear import of phosphorylated Mad. supporting_text: >- The screen identified moleskin (msk) as important for the nuclear import of phosphorylated Mad. - order: 4 role: nodal smad output node: id: nodal_smad_output label: Nodal SMAD output module_type: REGULATORY_STEP description: SMAD2/3 and SMAD4 mediate Nodal-dependent transcriptional control. annotons: - id: smad2_smad2_transcriptional_effector label: SMAD2 transcriptional effector participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SMAD2 term: id: UniProtKB:Q15796 label: SMAD family member 2 (SMAD 2) (hSMAD2) (JV18-1) (Mad-related protein 2) (hMAD-2) (Mothers against decapentaplegic homolog 2) (MAD homolog 2) (Mothers against DPP homolog 2) role_description: Curated exemplar for the smad2 transcriptional effector role in nodal signaling pathway. - id: smad3_smad3_transcriptional_effector label: SMAD3 transcriptional effector participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SMAD3 term: id: UniProtKB:P84022 label: SMAD family member 3 (SMAD 3) (hSMAD3) (JV15-2) (Mothers against decapentaplegic homolog 3) (MAD homolog 3) (Mad3) (Mothers against DPP homolog 3) (hMAD-3) role_description: Curated exemplar for the smad3 transcriptional effector role in nodal signaling pathway. - 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 nodal signaling pathway. connections: - source: nodal_coreceptor_engagement target: nodal_receptor_activation connection_type: CAUSES description: The initiating event promotes nodal receptor activation. - source: nodal_receptor_activation target: nodal_smad_nuclear_import connection_type: PRECEDES description: Receptor-phosphorylated SMAD2/3 leave the receptor and bind SMAD4, the cargo of nuclear import. - source: nodal_smad_nuclear_import target: nodal_smad_output connection_type: PROVIDES_INPUT_FOR description: Nuclear SMAD2/3-SMAD4 complexes regulate Nodal target genes.