Canonical activin receptor-SMAD signaling pathway module

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.

MODULE:activin_receptor_signalingCOMPLETESignaling Pathwaymodules/activin_receptor_signaling.yaml
activin receptor signaling pathwayGO:0032924
PMID:30540228
Activin A in Mammalian Physiology.
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.
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.
PMID:27328872
Activins and Inhibins: Roles in Development, Physiology, and Disease.
The comparative review places receptor phosphorylation, R-SMAD/co-SMAD assembly and nuclear transcription in the canonical relay.
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
PMID:38124338
Bone morphogenetic protein signaling: the pathway and its regulation.
The activin and BMP branches share type II receptors, while their usual type I/R-Smad pairings distinguish pathway output.
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.
PMID:22651914
Structural studies of the TGF-βs and their receptors - insights into evolution of the TGF-β superfamily.
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.
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.
PMID:34520530
Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs.
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.
These include the activins (Act A, B, and AB) and GDF11, both of which signal through the ActRII receptors, ActRIIa and ActRIIb
PMID:18820452
Distinct signaling of Drosophila Activin/TGF-beta family members.
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.
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.

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.

6Nodes
5Parts
0Variant Sets
0Variants
5Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

  • activin_receptor_signaling-deep-research-falcon.md (falcon)

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • r_smad_phosphorylation → activin_smad_nuclear_import [NOT_CHECKED]

Function consistency and core coverage

11 gene-function check(s) reflected in core functions · 0 conflict(s) · 11 evidence or coverage gap(s) (22 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
activin_ligand INHBA (human)
UniProtKB:P08476
Family Representative 		cytokine activity
GO:0005125 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_ligand Actbeta (Drosophila)
UniProtKB:O61643
Family Representative 		cytokine activity
GO:0005125 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_type_ii_receptor ACVR2A (human)
UniProtKB:P27037
Family Representative 		activin receptor activity, type II
GO:0016362 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_type_ii_receptor put (Drosophila)
UniProtKB:Q24468
Family Representative 		activin receptor activity, type II
GO:0016362 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_type_i_receptor ACVR1B (human)
UniProtKB:P36896
Family Representative 		activin receptor activity, type I
GO:0016361 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_type_i_receptor babo (Drosophila)
UniProtKB:A1Z7L8
Family Representative 		activin receptor activity, type I
GO:0016361 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_r_smad SMAD2 (human)
UniProtKB:Q15796
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_r_smad SMAD3 (human)
UniProtKB:P84022
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_r_smad Smox (Drosophila)
UniProtKB:O96660
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_co_smad SMAD4 (human)
UniProtKB:Q13485
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_co_smad Med (Drosophila)
UniProtKB:O62609
Family Representative 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
activin_ligand Activin agonist ligand subfamilies
PANTHER:PTHR11848:SF133
Family 		cytokine activity
GO:0005125 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11848:SF133.
activin_ligand Activin agonist ligand subfamilies
PANTHER:PTHR11848:SF309
Family 		cytokine activity
GO:0005125 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11848:SF309.
activin_type_ii_receptor Activin type II receptor subfamilies
PANTHER:PTHR23255:SF64
Family 		activin receptor activity, type II
GO:0016362 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR23255:SF64.
activin_type_ii_receptor Activin type II receptor subfamilies
PANTHER:PTHR23255:SF98
Family 		activin receptor activity, type II
GO:0016362 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR23255:SF98.
activin_type_i_receptor Activin type I receptor subfamilies
PANTHER:PTHR23255:SF22
Family 		activin receptor activity, type I
GO:0016361 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR23255:SF22.
activin_type_i_receptor Activin type I receptor subfamilies
PANTHER:PTHR23255:SF71
Family 		activin receptor activity, type I
GO:0016361 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR23255:SF71.
activin_r_smad Activin-branch receptor-regulated SMAD subfamilies
PANTHER:PTHR13703:SF42
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR13703:SF42.
activin_r_smad Activin-branch receptor-regulated SMAD subfamilies
PANTHER:PTHR13703:SF53
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR13703:SF53.
activin_r_smad Activin-branch receptor-regulated SMAD subfamilies
PANTHER:PTHR13703:SF25
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR13703:SF25.
activin_co_smad Common SMAD transcriptional partner subfamilies
PANTHER:PTHR13703:SF63
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR13703:SF63.
activin_co_smad Common SMAD transcriptional partner subfamilies
PANTHER:PTHR13703:SF45
Family 		DNA-binding transcription factor activity, RNA polymerase II-specific
GO:0000981 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR13703:SF45.

Gene-review completeness (11/11 grounded genes reviewed)

2 complete review(s) · 6 with deep research · 0 missing review · 5 reviewed but lacking deep research

Gene Review Complete Deep research
Actbeta O61643 ✓ ✓ ✓
ACVR1B P36896 ✓ 79/81 ✗
ACVR2A P27037 ✓ 97/102 ✗
babo A1Z7L8 ✓ ✓ ✓
INHBA P08476 ✓ 94/104 ✗
Med O62609 ✓ 82/87 ✓
put Q24468 ✓ 79/83 ✓
SMAD2 Q15796 ✓ 283/284 ✗
SMAD3 P84022 ✓ 333/349 ✓
SMAD4 Q13485 ✓ 422/428 ✗
Smox O96660 ✓ 70/71 ✓

Details

Context
Metazoan lineages retaining an activin-like receptor/SMAD relayNCBITaxon:33208
extracellular regionGO:0005576 plasma membraneGO:0005886 nucleusGO:0005634
PMID:28130362
TGF-β Family Signaling in Drosophila.
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.
PMID:38124338
Bone morphogenetic protein signaling: the pathway and its regulation.
The activin and BMP branches share type II receptors, while their usual type I/R-Smad pairings distinguish pathway output.
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.
PMID:22651914
Structural studies of the TGF-βs and their receptors - insights into evolution of the TGF-β superfamily.
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.
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.
PMID:19192293
Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom.
Comparative phylogenomics reconstructs ancient SMAD pathway machinery in nonbilaterian and bilaterian lineages; it does not establish native activin ligand coupling in each animal.
ancestral eumetazoan repertoire of four Smads, forming the basis of the pathway in the Placozoa, the Cnidaria, the Arthropoda, and in the Lophotrochozoa.
PMID:23020873
Conservation and evolutionary divergence in the activity of receptor-regulated smads.
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.
ligand-independent overexpression of either Xenopus or Nematostella Smad2/3

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.

Canonical activin receptor-SMAD signalingSignaling Pathwayactivin_receptor_signaling
activin receptor signaling pathwayGO:0032924
Context
Metazoan lineages retaining an activin-like receptor/SMAD relayNCBITaxon:33208
extracellular regionGO:0005576 plasma membraneGO:0005886 nucleusGO:0005634
PMID:28130362
TGF-β Family Signaling in Drosophila.
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.
PMID:38124338
Bone morphogenetic protein signaling: the pathway and its regulation.
The activin and BMP branches share type II receptors, while their usual type I/R-Smad pairings distinguish pathway output.
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.
PMID:22651914
Structural studies of the TGF-βs and their receptors - insights into evolution of the TGF-β superfamily.
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.
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.
PMID:19192293
Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom.
Comparative phylogenomics reconstructs ancient SMAD pathway machinery in nonbilaterian and bilaterian lineages; it does not establish native activin ligand coupling in each animal.
ancestral eumetazoan repertoire of four Smads, forming the basis of the pathway in the Placozoa, the Cnidaria, the Arthropoda, and in the Lophotrochozoa.
PMID:23020873
Conservation and evolutionary divergence in the activity of receptor-regulated smads.
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.
ligand-independent overexpression of either Xenopus or Nematostella Smad2/3

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.

PMID:19766717
The Drosophila Activin-like ligand Dawdle signals preferentially through one isoform of the Type-I receptor Baboon.
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.
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.
PMID:19766717
The Drosophila Activin-like ligand Dawdle signals preferentially through one isoform of the Type-I receptor Baboon.
Punt and Wit are not interchangeable for every activin-family ligand.
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.
PMID:10746731
Betaglycan binds inhibin and can mediate functional antagonism of activin signalling.
Inhibin antagonism is a distinct boundary mechanism: the inhibin-bound type II receptor fails to recruit the activin type I receptor.
Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin.
PMID:35736809
The orphan ligand, activin C, signals through activin receptor-like kinase 7.
Activin C and AC are active ALK7 ligands; the older inference that activin C is only an antagonist cannot define the family boundary.
ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7).
PMID:38533769
Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7.
Activin E signals through ALK7 and the canonical type II receptors; its branch has distinct antagonist sensitivity.
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.
PMID:39595638
Activins and Inhibins in Cardiovascular Pathophysiology.
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.

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.

Connections

Agonist binding promotes productive receptor complex assembly and signaling.
PMID:1314589
Molecular cloning and binding properties of the human type II activin receptor.
Cloned human ACVR2A directly binds activin A through its extracellular domain.
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.
PMID:9032295
Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation.
Human cell receptor-expression experiments resolve ligand-induced type I/type II heteromer formation.
We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner.
PMID:18820452
Distinct signaling of Drosophila Activin/TGF-beta family members.
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.
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.
Type II kinase-dependent GS-domain phosphorylation enables type I receptor signaling to R-SMADs.
PMID:8721982
Formation and activation by phosphorylation of activin receptor complexes.
Functional type II receptor is required for phosphorylation of the type I receptor GS domain.
Phosphorylation of the GS domain was dependent upon a functional ActRII.
PMID:8622651
Activation of signalling by the activin receptor complex.
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.
In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.
PMID:9887103
The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development.
Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly.
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.
Receptor-phosphorylated R-SMADs are released into the cytoplasm and assemble with co-SMADs, the cargo of nuclear import.
PMID:9892009
Roles of pathway-specific and inhibitory Smads in activin receptor signaling.
Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription.
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.
PMID:9887103
The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development.
Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly.
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.
PMID:10320478
Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals.
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.
dSMAD2 complexes with MEDEA only in the presence of ATR-I and PUNT.
PMID:31582430
Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling.
Activated SMAD2/3-SMAD4 assemblies regulate target genes through nuclear coactivator and repressor recruitment.
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.
Nuclear R-SMAD/co-SMAD complexes regulate activin target genes.
Part 1: Mature activin agonist signaling
Mature activin agonist signalingRegulatory Stepagonist_signal

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.

PMID:30540228
Activin A in Mammalian Physiology.
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.
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.
PMID:18820452
Distinct signaling of Drosophila Activin/TGF-beta family members.
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.
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.

Annotons

Activin agonist ligand subfamilies
activin_ligand
Participant: Family: Activin agonist ligand subfamilies
Family:
Activin agonist ligand subfamilies 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.
Representative Members: INHBA (human)UniProtKB:P08476 Actbeta (Drosophila)UniProtKB:O61643
Required Function:
cytokine activityGO:0005125

Function

cytokine activityGO:0005125

Processes

activin receptor signaling pathwayGO:0032924

Locations

extracellular regionGO:0005576

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.

PMID:30540228
Activin A in Mammalian Physiology.
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.
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.
PMID:18820452
Distinct signaling of Drosophila Activin/TGF-beta family members.
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.
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.
PMID:10652306
Identification of a binding site on the type II activin receptor for activin and inhibin.
Type II receptor ligand-binding residues are required for productive activin receptor signaling.
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.
PMID:12660162
Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions.
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.
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.
Part 2: Type II receptor engagement and type I activation
Type II receptor engagement and type I activationRegulatory Steptype_ii_receptor_activation

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.

PMID:1314589
Molecular cloning and binding properties of the human type II activin receptor.
Cloned human ACVR2A directly binds activin A through its extracellular domain.
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.
PMID:9032295
Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation.
Human cell receptor-expression experiments resolve ligand-induced type I/type II heteromer formation.
We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner.
PMID:8721982
Formation and activation by phosphorylation of activin receptor complexes.
Functional type II receptor is required for phosphorylation of the type I receptor GS domain.
Phosphorylation of the GS domain was dependent upon a functional ActRII.
PMID:18820452
Distinct signaling of Drosophila Activin/TGF-beta family members.
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.
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.

Annotons

Activin type II receptor subfamilies
activin_type_ii_receptor
Participant: Family: Activin type II receptor subfamilies
Family:
Activin type II receptor subfamilies 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.
Representative Members: ACVR2A (human)UniProtKB:P27037 put (Drosophila)UniProtKB:Q24468
Required Function:
activin receptor activity, type IIGO:0016362

Function

activin receptor activity, type IIGO:0016362

Processes

activin receptor signaling pathwayGO:0032924

Locations

plasma membraneGO:0005886

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.

PMID:1314589
Molecular cloning and binding properties of the human type II activin receptor.
Cloned human ACVR2A directly binds activin A through its extracellular domain.
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.
PMID:8721982
Formation and activation by phosphorylation of activin receptor complexes.
Functional type II receptor is required for phosphorylation of the type I receptor GS domain.
Phosphorylation of the GS domain was dependent upon a functional ActRII.
PMID:18820452
Distinct signaling of Drosophila Activin/TGF-beta family members.
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.
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.
PMID:38124338
Bone morphogenetic protein signaling: the pathway and its regulation.
The activin and BMP branches share type II receptors, while their usual type I/R-Smad pairings distinguish pathway output.
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.
Part 3: Type I receptor phosphorylation of R-SMADs
Type I receptor phosphorylation of R-SMADsRegulatory Stepr_smad_phosphorylation

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.

PMID:8622651
Activation of signalling by the activin receptor complex.
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.
In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.
PMID:9887103
The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development.
Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly.
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.
PMID:9892009
Roles of pathway-specific and inhibitory Smads in activin receptor signaling.
Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription.
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.

Annotons

Activin type I receptor subfamilies
activin_type_i_receptor
Participant: Family: Activin type I receptor subfamilies
Family:
Activin type I receptor subfamilies 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.
Representative Members: ACVR1B (human)UniProtKB:P36896 babo (Drosophila)UniProtKB:A1Z7L8
Required Function:
activin receptor activity, type IGO:0016361

Function

activin receptor activity, type IGO:0016361

Processes

activin receptor signaling pathwayGO:0032924

Locations

plasma membraneGO:0005886

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.

PMID:8622651
Activation of signalling by the activin receptor complex.
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.
In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.
PMID:9887103
The Drosophila activin receptor baboon signals through dSmad2 and controls cell proliferation but not patterning during larval development.
Activated Babo phosphorylates the Smox C-terminal motif and promotes Smox-Medea assembly.
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.
PMID:18820452
Distinct signaling of Drosophila Activin/TGF-beta family members.
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.
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.
PMID:19766717
The Drosophila Activin-like ligand Dawdle signals preferentially through one isoform of the Type-I receptor Baboon.
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.
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.
Part 4: R-SMAD nuclear import
R-SMAD/co-SMAD nuclear importTransport Stepactivin_smad_nuclear_import

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.

Realized by module karyopherin_nuclear_protein_import

PMID:11294908
Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner.
Receptor-activated SMAD3 binds importin-beta1 through its N-terminal domain; SMAD2 does not.
Smad3, via its N-terminal domain, interacts specifically with importin-beta1 and only after activation by receptor.
PMID:17785517
Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads.
Importin-7 and importin-8 are needed for nuclear accumulation of activated SMAD2/3; their fly orthologue Moleskin imports phosphorylated Mad.
markedly impaired nuclear accumulation of Smad1 in response to BMP2 and of Smad2/3 in response to TGF-beta.
PMID:17785517
Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads.
Moleskin, the Drosophila importin-7 orthologue, is required for nuclear import of phosphorylated Mad.
The screen identified moleskin (msk) as important for the nuclear import of phosphorylated Mad.
Part 5: R-SMAD/co-SMAD transcriptional output
R-SMAD/co-SMAD transcriptional outputRegulatory Stepactivin_transcription

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.

PMID:9892009
Roles of pathway-specific and inhibitory Smads in activin receptor signaling.
Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription.
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.
PMID:10320478
Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals.
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.
dSMAD2 complexes with MEDEA only in the presence of ATR-I and PUNT.
PMID:10320478
Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals.
Receptor-dependent Smox phosphorylation is associated with nuclear translocation.
dSMAD2 is phosphorylated by ATR-I and PUNT, but not by activated THICK VEINS, and translocates to the nucleus upon activation.
PMID:31582430
Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling.
Activated SMAD2/3-SMAD4 assemblies regulate target genes through nuclear coactivator and repressor recruitment.
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.

Annotons

Activin-branch receptor-regulated SMAD subfamilies
activin_r_smad
Participant: Family: Activin-branch receptor-regulated SMAD subfamilies
Family:
Activin-branch receptor-regulated SMAD subfamilies The human SMAD2/SMAD3 and fly Smox subfamilies supply the activin-branch R-SMAD role, distinct from BMP-branch SMAD1/5/9 or Mad.
Representative Members: SMAD2 (human)UniProtKB:Q15796 SMAD3 (human)UniProtKB:P84022 Smox (Drosophila)UniProtKB:O96660
Required Function:
DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Processes

activin receptor signaling pathwayGO:0032924

Locations

nucleusGO:0005634

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.

PMID:9892009
Roles of pathway-specific and inhibitory Smads in activin receptor signaling.
Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription.
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.
PMID:31582430
Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling.
Properly folded full-length SMAD2 can bind DNA; exon 3 modulates conformation and affinity rather than imposing an absolute inability to bind.
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.
PMID:9732876
Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription.
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.
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.
PMID:24244197
Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila.
Smox DNA binding is directly assayed in fly protein, independently of analogy to mammalian SMAD2/3.
EMSA analysis reveals that recombinant Smox protein (MH1-DNA binding domain) binds to Smad binding element (AGAC AGAC) located in Atg8a promoter.
Common SMAD transcriptional partner subfamilies
activin_co_smad
Participant: Family: Common SMAD transcriptional partner subfamilies
Family:
Common SMAD transcriptional partner subfamilies 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.
Representative Members: SMAD4 (human)UniProtKB:Q13485 Med (Drosophila)UniProtKB:O62609
Required Function:
DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Processes

activin receptor signaling pathwayGO:0032924

Locations

nucleusGO:0005634

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.

PMID:9892009
Roles of pathway-specific and inhibitory Smads in activin receptor signaling.
Activin receptor-associated SMAD2/3 subsequently associate with SMAD4 and mediate activin-induced transcription.
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.
PMID:10320478
Drosophila dSmad2 and Atr-I transmit activin/TGFbeta signals.
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.
dSMAD2 complexes with MEDEA only in the presence of ATR-I and PUNT.
PMID:31582430
Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling.
Activated SMAD2/3-SMAD4 assemblies regulate target genes through nuclear coactivator and repressor recruitment.
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.
PMID:31582430
Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling.
Full-length human SMAD4 directly binds a Gsc promoter DNA probe, complementing the complex-assembly evidence.
the full-length SMAD4 protein bound the Gsc1 probe at values between 0.15 and 0.30 µM
PMID:9702198
Characterization of human FAST-1, a TGF beta and activin signal transducer.
Human FAST-1/SMAD-dependent activin response-element activation requires endogenous SMAD4 and ligand stimulation.
The hFAST-1-dependent activation of ARE was completely dependent on endogenous Smad4 and stimulation by a TGF beta-like ligand.
PMID:15350224
Structural basis of heteromeric smad protein assembly in TGF-beta signaling.
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.
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.
PMID:20010841
A conserved activation element in BMP signaling during Drosophila development.
Medea contributes direct DNA-binding transcriptional regulation in the BMP branch; its activin complex role is independently established with Smox.
activating input by the Smad signal transducers Mothers against Dpp (Mad) and Medea via competitive DNA binding.