id: MODULE:activin_receptor_signaling title: Canonical activin receptor-SMAD signaling pathway module description: Mature activin agonists organize type II/type I serine/threonine kinase receptor complexes. Type II receptors activate type I receptors, which phosphorylate activin-branch R-SMADs; R-SMAD/co-SMAD complexes then regulate nuclear transcription. Human activin A and native Drosophila Actbeta provide complementary examples, with ligand-specific receptor usage and shared BMP components explicitly distinguished. status: COMPLETE evidence: - source_id: PMID:30540228 title: Activin A in Mammalian Physiology. statement: Activin beta-subunit dimers and inhibin alpha/beta dimers have distinct signaling identities; the agonist role here denotes mature activin, not every INHBA-containing complex. supporting_text: Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. - source_id: PMID:27328872 title: 'Activins and Inhibins: Roles in Development, Physiology, and Disease.' statement: The comparative review places receptor phosphorylation, R-SMAD/co-SMAD assembly and nuclear transcription in the canonical relay. supporting_text: Phosphorylation of R-Smads triggers the association with Smad4, which is common to all R-Smad complexes, followed by a shift in homeostasis toward the nucleus to activate or inhibit the transcription of downstream target genes - source_id: PMID:38124338 title: 'Bone morphogenetic protein signaling: the pathway and its regulation.' statement: The activin and BMP branches share type II receptors, while their usual type I/R-Smad pairings distinguish pathway output. supporting_text: in Drosophila, Tkv and Sax primarily mediate BMP signals to phosphorylate Mad, while Babo transduces Activin signals, phosphorylating Smox (dSmad2). However, both Drosophila type II receptors, Punt and Wit, clearly mediate signals from both branches. - source_id: PMID:22651914 title: Structural studies of the TGF-βs and their receptors - insights into evolution of the TGF-β superfamily. statement: Structural comparisons support related but distinct receptor-assembly mechanisms across the TGF-beta, BMP and activin groups; family membership alone does not determine ligand specificity. supporting_text: These structures underscore the shared ancestry of the TGF-βs with the BMPs and activins, but also provide insight as to how the TGF-βs diverged from the BMPs and activins to bind and assemble their receptors in a distinct manner. - source_id: PMID:34520530 title: Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs. statement: The ligand/receptor system is broader than activin A alone; activins, myostatin and GDF11 share receptor components, so the examples here are not a universal one-to-one ligand/receptor map. supporting_text: These include the activins (Act A, B, and AB) and GDF11, both of which signal through the ActRII receptors, ActRIIa and ActRIIb - source_id: PMID:18820452 title: Distinct signaling of Drosophila Activin/TGF-beta family members. statement: Native Drosophila Actbeta/dACT and Daw drive Babo/Punt-dependent Smox activation in the tested system. This establishes native ligand wiring rather than relying only on vertebrate activin in heterologous assays. supporting_text: Only Drosophila Activin (dACT) and the Activin-like ligand Dawdle (DAW) signal through BABO in combination with the type II receptor PUNT and activate dSMAD2. notes: Nuclear entry step (2026-11-10) - R-SMAD/co-SMAD nuclear import is now an explicit step, included by module_ref to karyopherin_nuclear_protein_import, so that the module states what GO-CAM activin-branch models compress into a receptor -> nuclear SMAD edge; GO-CAM ALK4/ALK7 and SMAD2/3 activities from the Activin A, Activin E, BMP3, BMP3b/GDF10 and BMP8B models are pinned. Metazoa is a non-universal taxonomic envelope for the conserved signaling toolkit, not a claim that every animal has this complete native ligand-receptor relay. Directly matched ligand/receptor/SMAD examples in this audit are human and Drosophila. Family selectors join verified narrow PANTHER subfamilies with an explicit required function; they do not propagate an activin role over the broad TGF-beta, receptor-kinase or SMAD parent families. The old PTN000218063 anchor is omitted because its extracellular-region and broad TGF-beta-process support did not establish the specific activin agonist role at an ancestral node. The original Falcon report is retained as a research lead, not used as primary evidence. All 11 representative genes are being reviewed in the same change. module: id: activin_receptor_signaling label: Canonical activin receptor-SMAD signaling module_type: SIGNALING_PATHWAY concepts: - preferred_term: activin receptor signaling pathway term: id: GO:0032924 label: activin receptor signaling pathway context: taxa: - preferred_term: Metazoan lineages retaining an activin-like receptor/SMAD relay term: id: NCBITaxon:33208 label: Metazoa description: A toolkit envelope with native complete-relay evidence in the reviewed bilaterian exemplars; neither universal retention nor an origin at the bilaterian ancestor is asserted. cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: nucleus term: id: GO:0005634 label: nucleus evidence: - source_id: PMID:28130362 title: TGF-β Family Signaling in Drosophila. statement: Comparative Drosophila review of the Babo-Smox activin branch and shared receptor/co-Smad components; used alongside native-ligand primary evidence and isoform-specific experiments. - source_id: PMID:38124338 title: 'Bone morphogenetic protein signaling: the pathway and its regulation.' statement: The activin and BMP branches share type II receptors, while their usual type I/R-Smad pairings distinguish pathway output. supporting_text: in Drosophila, Tkv and Sax primarily mediate BMP signals to phosphorylate Mad, while Babo transduces Activin signals, phosphorylating Smox (dSmad2). However, both Drosophila type II receptors, Punt and Wit, clearly mediate signals from both branches. - source_id: PMID:22651914 title: Structural studies of the TGF-βs and their receptors - insights into evolution of the TGF-β superfamily. statement: Structural comparisons support related but distinct receptor-assembly mechanisms across the TGF-beta, BMP and activin groups; family membership alone does not determine ligand specificity. supporting_text: These structures underscore the shared ancestry of the TGF-βs with the BMPs and activins, but also provide insight as to how the TGF-βs diverged from the BMPs and activins to bind and assemble their receptors in a distinct manner. - source_id: PMID:19192293 title: Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom. statement: Comparative phylogenomics reconstructs ancient SMAD pathway machinery in nonbilaterian and bilaterian lineages; it does not establish native activin ligand coupling in each animal. supporting_text: ancestral eumetazoan repertoire of four Smads, forming the basis of the pathway in the Placozoa, the Cnidaria, the Arthropoda, and in the Lophotrochozoa. - source_id: PMID:23020873 title: Conservation and evolutionary divergence in the activity of receptor-regulated smads. statement: Nematostella SMAD2/3 signaling competence was assayed by heterologous expression in Xenopus. This supports an ancient intracellular toolkit without demonstrating a native cnidarian activin-receptor relay. supporting_text: ligand-independent overexpression of either Xenopus or Nematostella Smad2/3 notes: Shared receptors and common SMADs also function in BMP/TGF-beta/Nodal pathways. Select an agonistic activin ligand and its compatible type I receptor rather than identifying this pathway from one homolog alone. parts: - order: 1 role: Mature activin agonist signaling node: id: agonist_signal label: Mature activin agonist signaling module_type: REGULATORY_STEP description: A secreted mature activin ligand initiates the canonical receptor relay. The human beta-A homodimer and native fly Actbeta illustrate distinct lineage-specific ligands; their sequences and receptor-binding specificities are not asserted to be identical. annotons: - id: activin_ligand label: Activin agonist ligand subfamilies participant: selector_type: FAMILY family: preferred_term: Activin agonist ligand subfamilies description: The verified human beta-A and fly Actbeta subfamilies anchor an activin agonist role; this is not blanket annotation of the TGF-beta superfamily or of all dimer combinations. family_terms: - id: PANTHER:PTHR11848:SF133 label: INHIBIN BETA A CHAIN - id: PANTHER:PTHR11848:SF309 label: INHIBIN BETA CHAIN representative_members: - preferred_term: INHBA (human) term: id: UniProtKB:P08476 label: Inhibin beta A chain - preferred_term: Actbeta (Drosophila) term: id: UniProtKB:O61643 label: Inhibin beta chain required_function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity processes: - preferred_term: activin receptor signaling pathway term: id: GO:0032924 label: activin receptor signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Contribute the cytokine activity of the mature secreted activin ligand. Human INHBA is represented in the activin A homodimer, not the inhibin A alpha/beta antagonist. Activity is not attributed to an unassembled precursor or single free chain. evidence: - source_id: PMID:30540228 title: Activin A in Mammalian Physiology. statement: Activin beta-subunit dimers and inhibin alpha/beta dimers have distinct signaling identities; the agonist role here denotes mature activin, not every INHBA-containing complex. supporting_text: Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. - source_id: PMID:18820452 title: Distinct signaling of Drosophila Activin/TGF-beta family members. statement: Native Drosophila Actbeta/dACT and Daw drive Babo/Punt-dependent Smox activation in the tested system. This establishes native ligand wiring rather than relying only on vertebrate activin in heterologous assays. supporting_text: Only Drosophila Activin (dACT) and the Activin-like ligand Dawdle (DAW) signal through BABO in combination with the type II receptor PUNT and activate dSMAD2. - source_id: PMID:10652306 title: Identification of a binding site on the type II activin receptor for activin and inhibin. statement: Type II receptor ligand-binding residues are required for productive activin receptor signaling. supporting_text: Unlike wild-type ActRII, the three mutants unable to bind activin do not cause an increase in activin signaling when transiently expressed in a corticotroph cell line. - source_id: PMID:12660162 title: Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions. statement: Structural analysis directly resolves the mature activin A ligand bound to a type II receptor; the ligand is a dimer rather than a free beta-A subunit. supporting_text: We have solved the crystal structure of activin A bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction. evidence: - source_id: PMID:30540228 title: Activin A in Mammalian Physiology. statement: Activin beta-subunit dimers and inhibin alpha/beta dimers have distinct signaling identities; the agonist role here denotes mature activin, not every INHBA-containing complex. supporting_text: Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. - source_id: PMID:18820452 title: Distinct signaling of Drosophila Activin/TGF-beta family members. statement: Native Drosophila Actbeta/dACT and Daw drive Babo/Punt-dependent Smox activation in the tested system. This establishes native ligand wiring rather than relying only on vertebrate activin in heterologous assays. supporting_text: Only Drosophila Activin (dACT) and the Activin-like ligand Dawdle (DAW) signal through BABO in combination with the type II receptor PUNT and activate dSMAD2. - order: 2 role: Type II receptor engagement and type I activation node: id: type_ii_receptor_activation label: Type II receptor engagement and type I activation module_type: REGULATORY_STEP description: Ligand binding organizes a productive type II/type I receptor assembly. Type II receptor kinase activity phosphorylates the type I GS domain; ligand-dependent assembly is not equated with creation of kinase activity de novo. annotons: - id: activin_type_ii_receptor label: Activin type II receptor subfamilies participant: selector_type: FAMILY family: preferred_term: Activin type II receptor subfamilies description: Human ACVR2A and fly Punt provide functionally comparable type II receptor examples; other type II receptors can substitute in specific ligand/tissue contexts but are not assumed interchangeable. family_terms: - id: PANTHER:PTHR23255:SF64 label: ACTIVIN RECEPTOR TYPE-2A - id: PANTHER:PTHR23255:SF98 label: SERINE_THREONINE-PROTEIN KINASE RECEPTOR representative_members: - preferred_term: ACVR2A (human) term: id: UniProtKB:P27037 label: Activin receptor type-2A - preferred_term: put (Drosophila) term: id: UniProtKB:Q24468 label: Serine/threonine-protein kinase receptor required_function: preferred_term: activin receptor activity, type II term: id: GO:0016362 label: activin receptor activity, type II function: preferred_term: activin receptor activity, type II term: id: GO:0016362 label: activin receptor activity, type II processes: - preferred_term: activin receptor signaling pathway term: id: GO:0032924 label: activin receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Bind agonist and participate in the receptor assembly whose type II kinase phosphorylates a type I receptor. These receptors are also used in BMP signaling, so family membership without ligand/type I context does not establish an activin-specific pathway. evidence: - source_id: PMID:1314589 title: Molecular cloning and binding properties of the human type II activin receptor. statement: Cloned human ACVR2A directly binds activin A through its extracellular domain. supporting_text: The type II human activin receptor consists of an extracellular domain that specifically binds activin A with a Kd of 360 pM, a single-membrane spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. - source_id: PMID:8721982 title: Formation and activation by phosphorylation of activin receptor complexes. statement: Functional type II receptor is required for phosphorylation of the type I receptor GS domain. supporting_text: Phosphorylation of the GS domain was dependent upon a functional ActRII. - source_id: PMID:18820452 title: Distinct signaling of Drosophila Activin/TGF-beta family members. statement: Native Drosophila Actbeta/dACT and Daw drive Babo/Punt-dependent Smox activation in the tested system. This establishes native ligand wiring rather than relying only on vertebrate activin in heterologous assays. supporting_text: Only Drosophila Activin (dACT) and the Activin-like ligand Dawdle (DAW) signal through BABO in combination with the type II receptor PUNT and activate dSMAD2. - source_id: PMID:38124338 title: 'Bone morphogenetic protein signaling: the pathway and its regulation.' statement: The activin and BMP branches share type II receptors, while their usual type I/R-Smad pairings distinguish pathway output. supporting_text: in Drosophila, Tkv and Sax primarily mediate BMP signals to phosphorylate Mad, while Babo transduces Activin signals, phosphorylating Smox (dSmad2). However, both Drosophila type II receptors, Punt and Wit, clearly mediate signals from both branches. gocam_associations: - model: gomodel:67b1629100002705 activity: gomodel:67b1629100002705/67b1629100002733 title: Activin A signaling pathway (Human) description: Curated human activity grounding; the module separately supplies cross-species and primary literature evidence. evidence: - source_id: PMID:1314589 title: Molecular cloning and binding properties of the human type II activin receptor. statement: Cloned human ACVR2A directly binds activin A through its extracellular domain. supporting_text: The type II human activin receptor consists of an extracellular domain that specifically binds activin A with a Kd of 360 pM, a single-membrane spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. - source_id: PMID:9032295 title: Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation. statement: Human cell receptor-expression experiments resolve ligand-induced type I/type II heteromer formation. supporting_text: We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner. - source_id: PMID:8721982 title: Formation and activation by phosphorylation of activin receptor complexes. statement: Functional type II receptor is required for phosphorylation of the type I receptor GS domain. supporting_text: Phosphorylation of the GS domain was dependent upon a functional ActRII. - source_id: PMID:18820452 title: Distinct signaling of Drosophila Activin/TGF-beta family members. statement: Native Drosophila Actbeta/dACT and Daw drive Babo/Punt-dependent Smox activation in the tested system. This establishes native ligand wiring rather than relying only on vertebrate activin in heterologous assays. supporting_text: Only Drosophila Activin (dACT) and the Activin-like ligand Dawdle (DAW) signal through BABO in combination with the type II receptor PUNT and activate dSMAD2. - order: 3 role: Type I receptor phosphorylation of R-SMADs node: id: r_smad_phosphorylation label: Type I receptor phosphorylation of R-SMADs gocam_associations: - model: gomodel:663d668500002824 activity: gomodel:663d668500002824/67b1629100002692 title: 'Activin E signaling pathway leading to inhibition of adipose tissue development (Human)' notes: ACVR1C (ALK7) type I receptor activity. ALK7 is an activin-branch type I receptor that is not among the type I annoton's representatives, so it is pinned to this step rather than to that annoton. module_type: REGULATORY_STEP description: The activated type I kinase phosphorylates the C-terminal R-SMAD motif. R-SMAD proteins are substrates of this step; their own transcriptional activities are represented in the downstream node. annotons: - id: activin_type_i_receptor label: Activin type I receptor subfamilies participant: selector_type: FAMILY family: preferred_term: Activin type I receptor subfamilies description: The ALK4 and Babo subfamilies ground the reviewed agonist relay. Ligand-dependent ALK7 alternatives are real, but the ALK4 exemplars do not stand for all activin type I receptor specificities. family_terms: - id: PANTHER:PTHR23255:SF22 label: ACTIVIN RECEPTOR TYPE-1B - id: PANTHER:PTHR23255:SF71 label: RECEPTOR PROTEIN SERINE_THREONINE KINASE representative_members: - preferred_term: ACVR1B (human) term: id: UniProtKB:P36896 label: Activin receptor type-1B - preferred_term: babo (Drosophila) term: id: UniProtKB:A1Z7L8 label: Receptor protein serine/threonine kinase required_function: preferred_term: activin receptor activity, type I term: id: GO:0016361 label: activin receptor activity, type I function: preferred_term: activin receptor activity, type I term: id: GO:0016361 label: activin receptor activity, type I processes: - preferred_term: activin receptor signaling pathway term: id: GO:0032924 label: activin receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Receive activating input from a type II receptor and phosphorylate the C-terminal motif of activin-branch R-SMADs. Fly gene-level Babo evidence spans isoforms; the canonical UniProt sequence is BaboB and is not proof that every assay used BaboB. evidence: - source_id: PMID:8622651 title: Activation of signalling by the activin receptor complex. statement: ActR-IIB kinase activity activates ActR-IB through its GS domain; this provides type-II-family mechanism evidence, not a claim that the experiment exclusively assayed ACVR2A. supporting_text: In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. - source_id: PMID:9887103 title: The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development. statement: Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly. supporting_text: Activated Babo associates with dSmad2 but not Mad, phosphorylates the carboxy-terminal SSXS motif and induces heteromeric complex formation with Medea, the Drosophila Smad4 homolog. - source_id: PMID:18820452 title: Distinct signaling of Drosophila Activin/TGF-beta family members. statement: Native Drosophila Actbeta/dACT and Daw drive Babo/Punt-dependent Smox activation in the tested system. This establishes native ligand wiring rather than relying only on vertebrate activin in heterologous assays. supporting_text: Only Drosophila Activin (dACT) and the Activin-like ligand Dawdle (DAW) signal through BABO in combination with the type II receptor PUNT and activate dSMAD2. - source_id: PMID:19766717 title: The Drosophila Activin-like ligand Dawdle signals preferentially through one isoform of the Type-I receptor Baboon. statement: Babo isoforms and type II receptor choice affect fly ligand specificity; the Daw/BaboC/Punt result must not be recast as proof of an exclusive Actbeta/BaboB pairing. supporting_text: Here, we show that Dawdle, one of four Activin-type ligands in Drosophila, preferentially signals through Babo(c), one of three isoforms of the Activin Type-I receptor that are expressed during development. gocam_associations: - model: gomodel:67b1629100002705 activity: gomodel:67b1629100002705/67b1629100002706 title: Activin A signaling pathway (Human) description: Curated human activity grounding; the module separately supplies cross-species and primary literature evidence. - model: gomodel:66e382fb00001097 activity: gomodel:66e382fb00001097/66e382fb00001121 title: BMP3 signaling leading to bone formation inhibition (Human) notes: ACVR1B (ALK4) activity; the ligand is a BMP-family member, but the receptor relay it drives (ALK4 phosphorylating SMAD2/3) is the activin-branch relay this element models. - model: gomodel:66e382fb00001148 activity: gomodel:66e382fb00001148/66e382fb00001166 title: 'BMP3b/GDF10 signaling leading to bone formation inhibition (Human)' notes: ACVR1B (ALK4) activity; the ligand is a BMP-family member, but the receptor relay it drives (ALK4 phosphorylating SMAD2/3) is the activin-branch relay this element models. - model: gomodel:66e382fb00002243 activity: gomodel:66e382fb00002243/671ae02600000617 title: BMP8B role in adipocyte differentiation inhibition (Human) notes: ACVR1B (ALK4) activity; the ligand is a BMP-family member, but the receptor relay it drives (ALK4 phosphorylating SMAD2/3) is the activin-branch relay this element models. evidence: - source_id: PMID:8622651 title: Activation of signalling by the activin receptor complex. statement: ActR-IIB kinase activity activates ActR-IB through its GS domain; this provides type-II-family mechanism evidence, not a claim that the experiment exclusively assayed ACVR2A. supporting_text: In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. - source_id: PMID:9887103 title: The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development. statement: Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly. supporting_text: Activated Babo associates with dSmad2 but not Mad, phosphorylates the carboxy-terminal SSXS motif and induces heteromeric complex formation with Medea, the Drosophila Smad4 homolog. - source_id: PMID:9892009 title: Roles of pathway-specific and inhibitory Smads in activin receptor signaling. statement: Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription. supporting_text: Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. - order: 4 role: R-SMAD nuclear import node: id: activin_smad_nuclear_import label: R-SMAD/co-SMAD 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). In Drosophila the importin-7 orthologue Moleskin is required for import of phosphorylated Mad (the BMP-branch R-SMAD); its use by Smox is inferred, not shown. 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: 5 role: R-SMAD/co-SMAD transcriptional output node: id: activin_transcription label: R-SMAD/co-SMAD transcriptional output module_type: REGULATORY_STEP description: Activated R-SMADs associate with a common SMAD, accumulate in the nucleus and regulate context-specific target transcription with additional DNA-binding factors, coactivators and repressors. This canonical complex-dependent output does not exhaust non-SMAD or SMAD4-independent activin effects. annotons: - id: activin_r_smad label: Activin-branch receptor-regulated SMAD subfamilies participant: selector_type: FAMILY family: preferred_term: Activin-branch receptor-regulated SMAD subfamilies description: The human SMAD2/SMAD3 and fly Smox subfamilies supply the activin-branch R-SMAD role, distinct from BMP-branch SMAD1/5/9 or Mad. family_terms: - id: PANTHER:PTHR13703:SF42 label: MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG 2 - id: PANTHER:PTHR13703:SF53 label: MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG 3 - id: PANTHER:PTHR13703:SF25 label: MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG representative_members: - preferred_term: SMAD2 (human) term: id: UniProtKB:Q15796 label: Mothers against decapentaplegic homolog 2 - preferred_term: SMAD3 (human) term: id: UniProtKB:P84022 label: Mothers against decapentaplegic homolog 3 - preferred_term: Smox (Drosophila) term: id: UniProtKB:O96660 label: Mothers against decapentaplegic homolog required_function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific processes: - preferred_term: activin receptor signaling pathway term: id: GO:0032924 label: activin receptor signaling pathway locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: Following receptor phosphorylation, bind DNA and transcriptional partners in nuclear activin-responsive complexes. SMAD2 DNA binding is conformation-dependent; human SMAD2/SMAD3 and fly Smox are not interchangeable in all target or developmental contexts. evidence: - source_id: PMID:9892009 title: Roles of pathway-specific and inhibitory Smads in activin receptor signaling. statement: Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription. supporting_text: Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. - source_id: PMID:31582430 title: Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling. statement: Properly folded full-length SMAD2 can bind DNA; exon 3 modulates conformation and affinity rather than imposing an absolute inability to bind. supporting_text: We observe that properly folded SMAD2 protein has intrinsic DNA-binding activity, which is modulated by the ensemble of conformations adopted by the E3 insert in solution. - source_id: PMID:9732876 title: Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. statement: Direct SMAD3 DNA binding and cooperative SMAD3/SMAD4 transcription provide molecular evidence from a TGF-beta context; activin participation is separately established by PMID:9892009. supporting_text: Here we show that Smad3 interacts directly with the TRE and that Smad3 and Smad4 can activate TGF-beta-inducible transcription from the TRE in the absence of c-Jun and c-Fos. - source_id: PMID:24244197 title: Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila. statement: Smox DNA binding is directly assayed in fly protein, independently of analogy to mammalian SMAD2/3. supporting_text: EMSA analysis reveals that recombinant Smox protein (MH1-DNA binding domain) binds to Smad binding element (AGAC AGAC) located in Atg8a promoter. gocam_associations: - model: gomodel:67b1629100002705 activity: gomodel:67b1629100002705/67b1629100002754 title: Activin A signaling pathway (Human) description: Curated human activity grounding; the module separately supplies cross-species and primary literature evidence. - model: gomodel:67b1629100002705 activity: gomodel:67b1629100002705/67b1629100002762 title: Activin A signaling pathway (Human) description: Curated human activity grounding; the module separately supplies cross-species and primary literature evidence. - model: gomodel:663d668500002824 activity: gomodel:663d668500002824/678073a900001657 title: 'Activin E signaling pathway leading to inhibition of adipose tissue development (Human)' notes: SMAD2 transcription factor activity in this model. - model: gomodel:663d668500002824 activity: gomodel:663d668500002824/678073a900001664 title: 'Activin E signaling pathway leading to inhibition of adipose tissue development (Human)' notes: SMAD3 transcription factor activity in this model. - model: gomodel:66e382fb00001097 activity: gomodel:66e382fb00001097/66e382fb00001132 title: BMP3 signaling leading to bone formation inhibition (Human) notes: SMAD2 transcription factor activity in this model. - model: gomodel:66e382fb00001097 activity: gomodel:66e382fb00001097/66e382fb00001139 title: BMP3 signaling leading to bone formation inhibition (Human) notes: SMAD3 transcription factor activity in this model. - model: gomodel:66e382fb00001148 activity: gomodel:66e382fb00001148/66e382fb00001177 title: 'BMP3b/GDF10 signaling leading to bone formation inhibition (Human)' notes: SMAD2 transcription factor activity in this model. - model: gomodel:66e382fb00001148 activity: gomodel:66e382fb00001148/66e382fb00001184 title: 'BMP3b/GDF10 signaling leading to bone formation inhibition (Human)' notes: SMAD3 transcription factor activity in this model. - model: gomodel:66e382fb00002243 activity: gomodel:66e382fb00002243/671ae02600000629 title: BMP8B role in adipocyte differentiation inhibition (Human) notes: SMAD2 transcription factor activity in this model. - model: gomodel:66e382fb00002243 activity: gomodel:66e382fb00002243/671ae02600000636 title: BMP8B role in adipocyte differentiation inhibition (Human) notes: SMAD3 transcription factor activity in this model. - id: activin_co_smad label: Common SMAD transcriptional partner subfamilies participant: selector_type: FAMILY family: preferred_term: Common SMAD transcriptional partner subfamilies description: Human SMAD4 and fly Medea are shared co-SMAD partners. The family is not activin-specific; the enclosing complex and pathway context determine the branch. family_terms: - id: PANTHER:PTHR13703:SF63 label: MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG 4 - id: PANTHER:PTHR13703:SF45 label: MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG representative_members: - preferred_term: SMAD4 (human) term: id: UniProtKB:Q13485 label: Mothers against decapentaplegic homolog 4 - preferred_term: Med (Drosophila) term: id: UniProtKB:O62609 label: Mothers against decapentaplegic homolog required_function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific processes: - preferred_term: activin receptor signaling pathway term: id: GO:0032924 label: activin receptor signaling pathway locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: Join receptor-regulated SMADs in DNA-associated transcriptional complexes and support activin-responsive gene regulation. SMAD4/Medea also serve the BMP branch; this role denotes the canonical co-SMAD-containing relay rather than every possible activin output. evidence: - source_id: PMID:9892009 title: Roles of pathway-specific and inhibitory Smads in activin receptor signaling. statement: Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription. supporting_text: Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. - source_id: PMID:10320478 title: Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals. statement: Fly Smox forms a complex with Medea in the receptor-dependent system; the study also uses Xenopus transcription assays, which are distinguished from native ligand evidence. supporting_text: dSMAD2 complexes with MEDEA only in the presence of ATR-I and PUNT. - source_id: PMID:31582430 title: Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling. statement: Activated SMAD2/3-SMAD4 assemblies regulate target genes through nuclear coactivator and repressor recruitment. supporting_text: Thus activated, SMAD2 and SMAD3 form complexes with SMAD4, accumulate in the nucleus, and recruit coactivators and repressors to regulate the expression of target genes. - source_id: PMID:31582430 title: Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling. statement: Full-length human SMAD4 directly binds a Gsc promoter DNA probe, complementing the complex-assembly evidence. supporting_text: the full-length SMAD4 protein bound the Gsc1 probe at values between 0.15 and 0.30 µM - source_id: PMID:9702198 title: Characterization of human FAST-1, a TGF beta and activin signal transducer. statement: Human FAST-1/SMAD-dependent activin response-element activation requires endogenous SMAD4 and ligand stimulation. supporting_text: The hFAST-1-dependent activation of ARE was completely dependent on endogenous Smad4 and stimulation by a TGF beta-like ligand. - source_id: PMID:15350224 title: Structural basis of heteromeric smad protein assembly in TGF-beta signaling. statement: Structurally characterized human SMAD2/SMAD4 and SMAD3/SMAD4 complexes contain two phosphorylated R-SMAD subunits and one SMAD4 subunit; this exact stoichiometry is not imposed on unmeasured fly complexes. supporting_text: Both complexes are heterotrimers, comprising two phosphorylated R-Smad subunits and one Smad4 subunit, a finding that was corroborated by isothermal titration calorimetry and mutational studies. - source_id: PMID:20010841 title: A conserved activation element in BMP signaling during Drosophila development. statement: Medea contributes direct DNA-binding transcriptional regulation in the BMP branch; its activin complex role is independently established with Smox. supporting_text: activating input by the Smad signal transducers Mothers against Dpp (Mad) and Medea via competitive DNA binding. evidence: - source_id: PMID:9892009 title: Roles of pathway-specific and inhibitory Smads in activin receptor signaling. statement: Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription. supporting_text: Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. - source_id: PMID:10320478 title: Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals. statement: Fly Smox forms a complex with Medea in the receptor-dependent system; the study also uses Xenopus transcription assays, which are distinguished from native ligand evidence. supporting_text: dSMAD2 complexes with MEDEA only in the presence of ATR-I and PUNT. - source_id: PMID:10320478 title: Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals. statement: Receptor-dependent Smox phosphorylation is associated with nuclear translocation. supporting_text: dSMAD2 is phosphorylated by ATR-I and PUNT, but not by activated THICK VEINS, and translocates to the nucleus upon activation. - source_id: PMID:31582430 title: Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling. statement: Activated SMAD2/3-SMAD4 assemblies regulate target genes through nuclear coactivator and repressor recruitment. supporting_text: Thus activated, SMAD2 and SMAD3 form complexes with SMAD4, accumulate in the nucleus, and recruit coactivators and repressors to regulate the expression of target genes. connections: - source: agonist_signal target: type_ii_receptor_activation connection_type: CAUSES description: Agonist binding promotes productive receptor complex assembly and signaling. evidence: - source_id: PMID:1314589 title: Molecular cloning and binding properties of the human type II activin receptor. statement: Cloned human ACVR2A directly binds activin A through its extracellular domain. supporting_text: The type II human activin receptor consists of an extracellular domain that specifically binds activin A with a Kd of 360 pM, a single-membrane spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. - source_id: PMID:9032295 title: Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation. statement: Human cell receptor-expression experiments resolve ligand-induced type I/type II heteromer formation. supporting_text: We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner. - source_id: PMID:18820452 title: Distinct signaling of Drosophila Activin/TGF-beta family members. statement: Native Drosophila Actbeta/dACT and Daw drive Babo/Punt-dependent Smox activation in the tested system. This establishes native ligand wiring rather than relying only on vertebrate activin in heterologous assays. supporting_text: Only Drosophila Activin (dACT) and the Activin-like ligand Dawdle (DAW) signal through BABO in combination with the type II receptor PUNT and activate dSMAD2. - source: type_ii_receptor_activation target: r_smad_phosphorylation connection_type: CAUSES description: Type II kinase-dependent GS-domain phosphorylation enables type I receptor signaling to R-SMADs. evidence: - source_id: PMID:8721982 title: Formation and activation by phosphorylation of activin receptor complexes. statement: Functional type II receptor is required for phosphorylation of the type I receptor GS domain. supporting_text: Phosphorylation of the GS domain was dependent upon a functional ActRII. - source_id: PMID:8622651 title: Activation of signalling by the activin receptor complex. statement: ActR-IIB kinase activity activates ActR-IB through its GS domain; this provides type-II-family mechanism evidence, not a claim that the experiment exclusively assayed ACVR2A. supporting_text: In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. - source_id: PMID:9887103 title: The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development. statement: Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly. supporting_text: Activated Babo associates with dSmad2 but not Mad, phosphorylates the carboxy-terminal SSXS motif and induces heteromeric complex formation with Medea, the Drosophila Smad4 homolog. - source: r_smad_phosphorylation target: activin_smad_nuclear_import connection_type: PRECEDES description: Receptor-phosphorylated R-SMADs are released into the cytoplasm and assemble with co-SMADs, the cargo of nuclear import. evidence: - source_id: PMID:9892009 title: Roles of pathway-specific and inhibitory Smads in activin receptor signaling. statement: Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription. supporting_text: Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. - source_id: PMID:9887103 title: The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development. statement: Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly. supporting_text: Activated Babo associates with dSmad2 but not Mad, phosphorylates the carboxy-terminal SSXS motif and induces heteromeric complex formation with Medea, the Drosophila Smad4 homolog. - source_id: PMID:10320478 title: Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals. statement: Fly Smox forms a complex with Medea in the receptor-dependent system; the study also uses Xenopus transcription assays, which are distinguished from native ligand evidence. supporting_text: dSMAD2 complexes with MEDEA only in the presence of ATR-I and PUNT. - source_id: PMID:31582430 title: Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling. statement: Activated SMAD2/3-SMAD4 assemblies regulate target genes through nuclear coactivator and repressor recruitment. supporting_text: Thus activated, SMAD2 and SMAD3 form complexes with SMAD4, accumulate in the nucleus, and recruit coactivators and repressors to regulate the expression of target genes. - source: activin_smad_nuclear_import target: activin_transcription connection_type: PROVIDES_INPUT_FOR description: Nuclear R-SMAD/co-SMAD complexes regulate activin target genes. gocam_associations: - model: gomodel:67b1629100002705 title: Activin A signaling pathway (Human) description: Curated human receptor and R-SMAD activities; the agonist is correctly modeled as activin A complex rather than a free INHBA chain. evidence: - source_id: PMID:19766717 title: The Drosophila Activin-like ligand Dawdle signals preferentially through one isoform of the Type-I receptor Baboon. statement: Babo isoforms and type II receptor choice affect fly ligand specificity; the Daw/BaboC/Punt result must not be recast as proof of an exclusive Actbeta/BaboB pairing. supporting_text: Here, we show that Dawdle, one of four Activin-type ligands in Drosophila, preferentially signals through Babo(c), one of three isoforms of the Activin Type-I receptor that are expressed during development. - source_id: PMID:19766717 title: The Drosophila Activin-like ligand Dawdle signals preferentially through one isoform of the Type-I receptor Baboon. statement: Punt and Wit are not interchangeable for every activin-family ligand. supporting_text: In cell culture, Dawdle signaling is active in the presence of the Type-II receptor Punt but not Wit, demonstrating that the Type-II receptor also contributes to the specificity of the signaling complex. - source_id: PMID:10746731 title: Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. statement: 'Inhibin antagonism is a distinct boundary mechanism: the inhibin-bound type II receptor fails to recruit the activin type I receptor.' supporting_text: Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin. - source_id: PMID:35736809 title: The orphan ligand, activin C, signals through activin receptor-like kinase 7. statement: Activin C and AC are active ALK7 ligands; the older inference that activin C is only an antagonist cannot define the family boundary. supporting_text: ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). - source_id: PMID:38533769 title: Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7. statement: Activin E signals through ALK7 and the canonical type II receptors; its branch has distinct antagonist sensitivity. supporting_text: ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. - source_id: PMID:39595638 title: Activins and Inhibins in Cardiovascular Pathophysiology. statement: The 2024 cardiovascular review provides tissue context but repeats an outdated C/E inactivity hypothesis. The module uses the direct ALK7 studies instead of that hypothesis. notes: The canonical agonist relay excludes inhibin antagonism as an initiating positive step, BMP-Mad output, Nodal-specific co-receptor requirements, and non-SMAD branches. These are real neighboring mechanisms, not false functions. ALK7-dependent activin C/E signaling and fly Babo isoform preferences show why ALK4/Babo examples cannot be generalized to all ligands. Human trimer stoichiometry is not imposed on fly complexes. Constitutive or overexpressed receptor assays are distinguished from native ligand assays. references: - id: PMID:30540228 title: Activin A in Mammalian Physiology. findings: - statement: Activin beta-subunit dimers and inhibin alpha/beta dimers have distinct signaling identities; the agonist role here denotes mature activin, not every INHBA-containing complex. supporting_text: Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Review used for comparative synthesis and boundaries; direct activity claims are also anchored in primary sources. full_text_unavailable: true - id: PMID:1314589 title: Molecular cloning and binding properties of the human type II activin receptor. findings: - statement: Cloned human ACVR2A directly binds activin A through its extracellular domain. supporting_text: The type II human activin receptor consists of an extracellular domain that specifically binds activin A with a Kd of 360 pM, a single-membrane spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:10652306 title: Identification of a binding site on the type II activin receptor for activin and inhibin. findings: - statement: Type II receptor ligand-binding residues are required for productive activin receptor signaling. supporting_text: Unlike wild-type ActRII, the three mutants unable to bind activin do not cause an increase in activin signaling when transiently expressed in a corticotroph cell line. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:8721982 title: Formation and activation by phosphorylation of activin receptor complexes. findings: - statement: Functional type II receptor is required for phosphorylation of the type I receptor GS domain. supporting_text: Phosphorylation of the GS domain was dependent upon a functional ActRII. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:8622651 title: Activation of signalling by the activin receptor complex. findings: - statement: ActR-IIB kinase activity activates ActR-IB through its GS domain; this provides type-II-family mechanism evidence, not a claim that the experiment exclusively assayed ACVR2A. supporting_text: In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:9032295 title: Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation. findings: - statement: Human cell receptor-expression experiments resolve ligand-induced type I/type II heteromer formation. supporting_text: We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:9892009 title: Roles of pathway-specific and inhibitory Smads in activin receptor signaling. findings: - statement: Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription. supporting_text: Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:18820452 title: Distinct signaling of Drosophila Activin/TGF-beta family members. findings: - statement: Native Drosophila Actbeta/dACT and Daw drive Babo/Punt-dependent Smox activation in the tested system. This establishes native ligand wiring rather than relying only on vertebrate activin in heterologous assays. supporting_text: Only Drosophila Activin (dACT) and the Activin-like ligand Dawdle (DAW) signal through BABO in combination with the type II receptor PUNT and activate dSMAD2. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Native dACT/Babo/Punt/Smox evidence is used. The assay-specific failure of Myoglianin to signal is not generalized into a family-wide exclusion, and activated-Babo/Mad crossover is not treated as the canonical branch. full_text_unavailable: true - id: PMID:9887103 title: The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development. findings: - statement: Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly. supporting_text: Activated Babo associates with dSmad2 but not Mad, phosphorylates the carboxy-terminal SSXS motif and induces heteromeric complex formation with Medea, the Drosophila Smad4 homolog. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:10320478 title: Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals. findings: - statement: Fly Smox forms a complex with Medea in the receptor-dependent system; the study also uses Xenopus transcription assays, which are distinguished from native ligand evidence. supporting_text: dSMAD2 complexes with MEDEA only in the presence of ATR-I and PUNT. - statement: Receptor-dependent Smox phosphorylation is associated with nuclear translocation. supporting_text: dSMAD2 is phosphorylated by ATR-I and PUNT, but not by activated THICK VEINS, and translocates to the nucleus upon activation. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:19766717 title: The Drosophila Activin-like ligand Dawdle signals preferentially through one isoform of the Type-I receptor Baboon. findings: - statement: Babo isoforms and type II receptor choice affect fly ligand specificity; the Daw/BaboC/Punt result must not be recast as proof of an exclusive Actbeta/BaboB pairing. supporting_text: Here, we show that Dawdle, one of four Activin-type ligands in Drosophila, preferentially signals through Babo(c), one of three isoforms of the Activin Type-I receptor that are expressed during development. - statement: Punt and Wit are not interchangeable for every activin-family ligand. supporting_text: In cell culture, Dawdle signaling is active in the presence of the Type-II receptor Punt but not Wit, demonstrating that the Type-II receptor also contributes to the specificity of the signaling complex. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. - id: PMID:31582430 title: Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling. findings: - statement: Properly folded full-length SMAD2 can bind DNA; exon 3 modulates conformation and affinity rather than imposing an absolute inability to bind. supporting_text: We observe that properly folded SMAD2 protein has intrinsic DNA-binding activity, which is modulated by the ensemble of conformations adopted by the E3 insert in solution. - statement: Activated SMAD2/3-SMAD4 assemblies regulate target genes through nuclear coactivator and repressor recruitment. supporting_text: Thus activated, SMAD2 and SMAD3 form complexes with SMAD4, accumulate in the nucleus, and recruit coactivators and repressors to regulate the expression of target genes. - statement: Full-length human SMAD4 directly binds a Gsc promoter DNA probe, complementing the complex-assembly evidence. supporting_text: the full-length SMAD4 protein bound the Gsc1 probe at values between 0.15 and 0.30 µM reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. - id: PMID:9702198 title: Characterization of human FAST-1, a TGF beta and activin signal transducer. findings: - statement: Human FAST-1/SMAD-dependent activin response-element activation requires endogenous SMAD4 and ligand stimulation. supporting_text: The hFAST-1-dependent activation of ARE was completely dependent on endogenous Smad4 and stimulation by a TGF beta-like ligand. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:9732876 title: Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. findings: - statement: Direct SMAD3 DNA binding and cooperative SMAD3/SMAD4 transcription provide molecular evidence from a TGF-beta context; activin participation is separately established by PMID:9892009. supporting_text: Here we show that Smad3 interacts directly with the TRE and that Smad3 and Smad4 can activate TGF-beta-inducible transcription from the TRE in the absence of c-Jun and c-Fos. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:24244197 title: Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila. findings: - statement: Smox DNA binding is directly assayed in fly protein, independently of analogy to mammalian SMAD2/3. supporting_text: EMSA analysis reveals that recombinant Smox protein (MH1-DNA binding domain) binds to Smad binding element (AGAC AGAC) located in Atg8a promoter. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. - id: PMID:20010841 title: A conserved activation element in BMP signaling during Drosophila development. findings: - statement: Medea contributes direct DNA-binding transcriptional regulation in the BMP branch; its activin complex role is independently established with Smox. supporting_text: activating input by the Smad signal transducers Mothers against Dpp (Mad) and Medea via competitive DNA binding. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:15350224 title: Structural basis of heteromeric smad protein assembly in TGF-beta signaling. findings: - statement: Structurally characterized human SMAD2/SMAD4 and SMAD3/SMAD4 complexes contain two phosphorylated R-SMAD subunits and one SMAD4 subunit; this exact stoichiometry is not imposed on unmeasured fly complexes. supporting_text: Both complexes are heterotrimers, comprising two phosphorylated R-Smad subunits and one Smad4 subunit, a finding that was corroborated by isothermal titration calorimetry and mutational studies. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:27328872 title: 'Activins and Inhibins: Roles in Development, Physiology, and Disease.' findings: - statement: The comparative review places receptor phosphorylation, R-SMAD/co-SMAD assembly and nuclear transcription in the canonical relay. supporting_text: Phosphorylation of R-Smads triggers the association with Smad4, which is common to all R-Smad complexes, followed by a shift in homeostasis toward the nucleus to activate or inhibit the transcription of downstream target genes - statement: The review proposes that activin C/E homodimers are unlikely to signal through activin receptors; this claim is superseded by direct ALK7 signaling studies. supporting_text: Activins C and E are unlikely to signal through activin receptors finding_review: finding_status: OVERTURNED superseded_by: - PMID:35736809 - PMID:38533769 review_notes: The blanket inactivity hypothesis is superseded; ligand-specific antagonism or heterodimer effects may still occur in other contexts. supported_by: - reference_id: PMID:35736809 supporting_text: ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). - reference_id: PMID:38533769 supporting_text: ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. reference_review: relevance: HIGH correctness: DISPUTED review_notes: 'Useful receptor/signaling synthesis, but the suggestion that activin C/E do not signal is outdated: primary PMID:35736809 and PMID:38533769 establish ALK7-mediated activity. Only independently supported portions are used here.' - id: PMID:38124338 title: 'Bone morphogenetic protein signaling: the pathway and its regulation.' findings: - statement: The activin and BMP branches share type II receptors, while their usual type I/R-Smad pairings distinguish pathway output. supporting_text: in Drosophila, Tkv and Sax primarily mediate BMP signals to phosphorylate Mad, while Babo transduces Activin signals, phosphorylating Smox (dSmad2). However, both Drosophila type II receptors, Punt and Wit, clearly mediate signals from both branches. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Review used for comparative synthesis and boundaries; direct activity claims are also anchored in primary sources. - id: PMID:28130362 title: TGF-β Family Signaling in Drosophila. findings: - statement: Comparative Drosophila review of the Babo-Smox activin branch and shared receptor/co-Smad components; used alongside native-ligand primary evidence and isoform-specific experiments. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Review used for comparative synthesis and boundaries; direct activity claims are also anchored in primary sources. full_text_unavailable: true - id: PMID:22651914 title: Structural studies of the TGF-βs and their receptors - insights into evolution of the TGF-β superfamily. findings: - statement: Structural comparisons support related but distinct receptor-assembly mechanisms across the TGF-beta, BMP and activin groups; family membership alone does not determine ligand specificity. supporting_text: These structures underscore the shared ancestry of the TGF-βs with the BMPs and activins, but also provide insight as to how the TGF-βs diverged from the BMPs and activins to bind and assemble their receptors in a distinct manner. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Review used for comparative synthesis and boundaries; direct activity claims are also anchored in primary sources. full_text_unavailable: true - id: PMID:34520530 title: Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs. findings: - statement: The ligand/receptor system is broader than activin A alone; activins, myostatin and GDF11 share receptor components, so the examples here are not a universal one-to-one ligand/receptor map. supporting_text: These include the activins (Act A, B, and AB) and GDF11, both of which signal through the ActRII receptors, ActRIIa and ActRIIb reference_review: relevance: HIGH correctness: VERIFIED review_notes: Review used for comparative synthesis and boundaries; direct activity claims are also anchored in primary sources. - id: PMID:10746731 title: Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. findings: - statement: 'Inhibin antagonism is a distinct boundary mechanism: the inhibin-bound type II receptor fails to recruit the activin type I receptor.' supporting_text: Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. full_text_unavailable: true - id: PMID:35736809 title: The orphan ligand, activin C, signals through activin receptor-like kinase 7. findings: - statement: Activin C and AC are active ALK7 ligands; the older inference that activin C is only an antagonist cannot define the family boundary. supporting_text: ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. - id: PMID:38533769 title: Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7. findings: - statement: Activin E signals through ALK7 and the canonical type II receptors; its branch has distinct antagonist sensitivity. supporting_text: ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. - id: PMID:39595638 title: Activins and Inhibins in Cardiovascular Pathophysiology. findings: - statement: The 2024 cardiovascular review provides tissue context but repeats an outdated C/E inactivity hypothesis. The module uses the direct ALK7 studies instead of that hypothesis. - statement: The review proposes that activin C/E homodimers are unlikely to signal through activin receptors; this claim is superseded by direct ALK7 signaling studies. supporting_text: Research suggests that βC and βE subunits, forming homodimers like activin C (βCβC) and activin E (βEβE), are unlikely to signal through activin receptors. finding_review: finding_status: OVERTURNED superseded_by: - PMID:35736809 - PMID:38533769 review_notes: The blanket inactivity hypothesis is superseded; ligand-specific antagonism or heterodimer effects may still occur in other contexts. supported_by: - reference_id: PMID:35736809 supporting_text: ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). - reference_id: PMID:38533769 supporting_text: ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. reference_review: relevance: MEDIUM correctness: DISPUTED review_notes: 'Useful receptor/signaling synthesis, but the suggestion that activin C/E do not signal is outdated: primary PMID:35736809 and PMID:38533769 establish ALK7-mediated activity. Only independently supported portions are used here.' - id: PMID:19192293 title: Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom. findings: - statement: Comparative phylogenomics reconstructs ancient SMAD pathway machinery in nonbilaterian and bilaterian lineages; it does not establish native activin ligand coupling in each animal. supporting_text: ancestral eumetazoan repertoire of four Smads, forming the basis of the pathway in the Placozoa, the Cnidaria, the Arthropoda, and in the Lophotrochozoa. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. - id: PMID:23020873 title: Conservation and evolutionary divergence in the activity of receptor-regulated smads. findings: - statement: Nematostella SMAD2/3 signaling competence was assayed by heterologous expression in Xenopus. This supports an ancient intracellular toolkit without demonstrating a native cnidarian activin-receptor relay. supporting_text: ligand-independent overexpression of either Xenopus or Nematostella Smad2/3 reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary evidence examined; species, ligand, assay and cross-pathway limits are stated in individual findings. - id: PMID:12660162 title: Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full-text primary ligand/receptor structure; distinguishes the mature activin A dimer from an unassembled precursor and from inhibitory alpha/beta dimers. findings: - statement: Structural analysis directly resolves the mature activin A ligand bound to a type II receptor; the ligand is a dimer rather than a free beta-A subunit. supporting_text: We have solved the crystal structure of activin A bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction.