id: MODULE:tgfb_smad_signaling title: TGF-beta receptor-SMAD signaling pathway module description: >- A compact TGF-beta/SMAD signaling module. A dimeric TGF-beta family ligand binds type II and type I serine/threonine kinase receptors, the type II receptor activates the type I receptor, the type I receptor phosphorylates receptor-regulated SMADs, and SMAD complexes accumulate in the nucleus to regulate transcription. The module is grounded in GO:0007179. TGFB1 is anchored to PAINT TGF-beta-family nodes; receptors and SMADs are included as curated UniProt exemplars without PTN ancestry where local seed rows were not available. status: DRAFT evidence: - source_id: GO:0007179 title: transforming growth factor beta receptor signaling pathway statement: The module is grounded in the GO biological process term for TGF-beta receptor signaling. module: id: tgfb_smad_signaling label: TGF-beta receptor-SMAD signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: transforming growth factor beta receptor signaling pathway term: id: GO:0007179 label: transforming growth factor beta receptor signaling pathway description: TGF-beta ligand to receptor-activated SMAD transcriptional response. 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: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: ligand and receptor complex formation node: id: tgfb_receptor_ligation label: TGF-beta ligand recruits type II/type I receptors gocam_associations: - model: gomodel:663d668500003144 activity: gomodel:663d668500003144/663d668500003152 title: TGFB1-mediated signaling pathway (Human) notes: TGFBR1 (the type I receptor kinase of the complex) activity in this model. - model: gomodel:663d668500003182 activity: gomodel:663d668500003182/663d668500003190 title: TGFB2-mediated signaling pathway (Human) notes: TGFBR1 (the type I receptor kinase of the complex) activity in this model. - model: gomodel:663d668500003232 activity: gomodel:663d668500003232/663d668500003240 title: TGFB3-mediated signaling pathway (Human) notes: TGFBR1 (the type I receptor kinase of the complex) activity in this model. - model: gomodel:671ae02600000676 activity: gomodel:671ae02600000676/671ae02600000718 title: GDF8 role in trophoblast invasion (Human) notes: TGFBR1 (the type I receptor kinase of the complex) activity in this model. module_type: REGULATORY_STEP description: >- Mature dimeric TGF-beta ligand assembles a heterotetrameric receptor complex containing type II and type I receptor serine/threonine kinases. annotons: - id: tgfb_ligand label: TGF-beta family ligand participant: selector_type: FAMILY family: preferred_term: TGF-beta family ligands term: id: PANTHER:PTHR11848 label: TGF-BETA FAMILY representative_members: - preferred_term: TGFB1 term: id: UniProtKB:P01137 label: Transforming growth factor beta-1 proprotein ancestral_nodes: - preferred_term: PAINT TGF-beta receptor-signaling node PTN000218722 term: id: PANTHER:PTN000218722 label: PTN000218722 description: >- PANTHER PAINT node in PTHR11848 with IBD support for transforming growth factor beta receptor signaling pathway (P:GO:0007179). evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000218722 in PTHR11848. - preferred_term: PAINT TGF-beta cytokine node PTN000218063 term: id: PANTHER:PTN000218063 label: PTN000218063 description: >- PANTHER PAINT node in PTHR11848 with IBD support for cytokine activity (F:GO:0005125), extracellular region, and TGF-beta receptor signaling participation. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000218063 in PTHR11848. function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity targets: - preferred_term: TGF-beta type II receptor - preferred_term: TGF-beta type I receptor processes: - preferred_term: transforming growth factor beta receptor signaling pathway term: id: GO:0007179 label: transforming growth factor beta receptor signaling pathway role_description: Extracellular dimeric ligand that nucleates receptor complex formation. - id: tgfb_receptors label: Type II/type I TGF-beta receptor kinases participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: TGF-beta receptor kinase complex description: TGFBR2 phosphorylates and activates TGFBR1/ALK5 in the ligand-bound receptor complex. active_units: - id: tgfbr2_unit label: TGFBR2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TGFBR2 term: id: UniProtKB:P37173 label: TGF-beta receptor type-2 role: type II receptor kinase - id: tgfbr1_unit label: TGFBR1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TGFBR1 term: id: UniProtKB:P36897 label: TGF-beta receptor type-1 role: type I receptor kinase that phosphorylates receptor-regulated SMADs function: preferred_term: transmembrane receptor protein serine/threonine kinase activity term: id: GO:0004675 label: transmembrane receptor protein serine/threonine kinase activity role_description: Ligand-assembled kinase complex that activates SMAD2/3. - order: 2 role: receptor-regulated SMAD phosphorylation node: id: r_smad_activation label: SMAD2/3 phosphorylation by activated type I receptor module_type: REACTION description: >- Activated TGFBR1 phosphorylates the C-terminal SSXS motif of SMAD2 and SMAD3, licensing complex formation with SMAD4. annotons: - id: r_smad_effectors label: Receptor-regulated SMADs participant: selector_type: FAMILY family: preferred_term: SMAD2/3 receptor-regulated SMADs representative_members: - preferred_term: SMAD2 term: id: UniProtKB:Q15796 label: SMAD family member 2 - preferred_term: SMAD3 term: id: UniProtKB:P84022 label: SMAD family member 3 role_description: Direct type I receptor substrates and signal carriers. - order: 3 role: SMAD2/3 nuclear import node: id: smad23_nuclear_import label: SMAD2/3 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. 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 TGF-beta-activated SMAD2/3. supporting_text: >- markedly impaired nuclear accumulation of Smad1 in response to BMP2 and of Smad2/3 in response to TGF-beta. - order: 4 role: nuclear SMAD transcriptional output node: id: smad_transcriptional_output label: SMAD2/3-SMAD4 nuclear transcriptional complexes gocam_associations: - model: gomodel:663d668500003144 activity: gomodel:663d668500003144/663d668500003164 title: TGFB1-mediated signaling pathway (Human) notes: SMAD2 activity in this model. - model: gomodel:663d668500003182 activity: gomodel:663d668500003182/663d668500003202 title: TGFB2-mediated signaling pathway (Human) notes: SMAD2 activity in this model. - model: gomodel:663d668500003232 activity: gomodel:663d668500003232/663d668500003252 title: TGFB3-mediated signaling pathway (Human) notes: SMAD2 activity in this model. - model: gomodel:671ae02600000676 activity: gomodel:671ae02600000676/671ae02600000695 title: GDF8 role in trophoblast invasion (Human) notes: SMAD2 activity in this model. - model: gomodel:671ae02600000676 activity: gomodel:671ae02600000676/671ae02600000702 title: GDF8 role in trophoblast invasion (Human) notes: SMAD3 activity in this model. module_type: REGULATORY_STEP description: >- Phosphorylated SMAD2/3 bind SMAD4 and partner transcription factors, accumulate in the nucleus, and regulate TGF-beta target genes. annotons: - id: 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 locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: Co-SMAD that forms nuclear complexes with phosphorylated receptor-regulated SMADs. connections: - source: tgfb_receptor_ligation target: r_smad_activation connection_type: CAUSES description: Ligand-bound receptors activate the type I kinase that phosphorylates SMAD2/3. - source: r_smad_activation target: smad23_nuclear_import connection_type: PRECEDES description: Phosphorylated SMAD2/3 leave the receptor, bind SMAD4 and are imported. - source: smad23_nuclear_import target: smad_transcriptional_output connection_type: PROVIDES_INPUT_FOR description: Nuclear SMAD2/3-SMAD4 complexes regulate TGF-beta target genes.