ACVR1B, also called ALK4 or ActRIB, is a single-pass type I membrane receptor with an intracellular serine/threonine kinase domain. It assembles with activin-bound type-II receptors ACVR2A or ACVR2B, which phosphorylate its regulatory GS domain. Activated ACVR1B phosphorylates SMAD2 and SMAD3 to couple extracellular ligand recognition to nuclear transcriptional responses. Its extracellular domain contacts activin within the assembled receptor complex, whereas the isolated type-I receptor does not efficiently capture ligand by itself. ACVR1B also transduces nodal signals with EGF-CFC coreceptors such as CRIPTO and can participate in myostatin/GDF signaling. These receptor pathways regulate cell growth, differentiation and developmental patterning, with context-dependent effects in erythroid, neural and trophoblast cells. FKBP12 and inhibitory SMAD7-associated complexes restrain receptor signaling; truncated kinase-domain isoforms can act as dominant-negative receptors.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000082 G1/S transition of mitotic cell cycle | IDA PMID:11117535 Truncated activin type I receptor Alk4 isoforms are dominant... | MODIFY | Summary: The human K562 study shows that intact ALK4 signaling produces growth inhibition and G1 accumulation, whereas truncated dominant-negative isoforms prevent these effects. Refine participation in the G1/S transition to negative regulation of that transition, rather than implying that ALK4 drives cell-cycle progression. Reason: The human K562 study shows that intact ALK4 signaling produces growth inhibition and G1 accumulation, whereas truncated dominant-negative isoforms prevent these effects. Refine participation in the G1/S transition to negative regulation of that transition, rather than implying that ALK4 drives cell-cycle progression. Proposed replacements: negative regulation of G1/S transition of mitotic cell cycle Supporting Evidence: PMID:11117535 activin administration failed to cause growth inhibition and an increase of the G1 population in these cells. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: ACVR1B is an integral transmembrane receptor serine/threonine kinase, so the existing receptor-specific kinase term is more informative than protein kinase activity. Reason: ACVR1B is an integral transmembrane receptor serine/threonine kinase, so the existing receptor-specific kinase term is more informative than protein kinase activity. Proposed replacements: transmembrane receptor protein serine/threonine kinase activity Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:11389842 Nodal signals to Smads through Cripto-dependent and Cripto-i... | MODIFY | Summary: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Reason: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Proposed replacements: transmembrane receptor protein serine/threonine kinase activity Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:12065756 SB-431542 is a potent and specific inhibitor of transforming... | MODIFY | Summary: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Reason: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Proposed replacements: transmembrane receptor protein serine/threonine kinase activity Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:18039968 Ttrap is an essential modulator of Smad3-dependent Nodal sig... | MODIFY | Summary: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Reason: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Proposed replacements: transmembrane receptor protein serine/threonine kinase activity Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000107 | MODIFY | Summary: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Reason: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Proposed replacements: transmembrane receptor protein serine/threonine kinase activity Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-1549526 | MODIFY | Summary: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Reason: The catalytic activity is executed by a transmembrane receptor. Refine to the existing receptor serine/threonine kinase term, supported by receptor activation and kinase-inhibitor experiments. This does not infer identical ligand specificity for all ALK family kinases. Proposed replacements: transmembrane receptor protein serine/threonine kinase activity Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0004675 transmembrane receptor protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ACVR1B is a transmembrane serine/threonine kinase receptor activated through its GS domain and coupled to SMAD2/3 signaling. The term appropriately captures the shared catalytic mechanism across activin, nodal and other ALK4-dependent ligand contexts. Reason: ACVR1B is a transmembrane serine/threonine kinase receptor activated through its GS domain and coupled to SMAD2/3 signaling. The term appropriately captures the shared catalytic mechanism across activin, nodal and other ALK4-dependent ligand contexts. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0004675 transmembrane receptor protein serine/threonine kinase activity | NAS PMID:9032295 Activin and inhibin have antagonistic effects on ligand-depe... | ACCEPT | Summary: ACVR1B is a transmembrane serine/threonine kinase receptor activated through its GS domain and coupled to SMAD2/3 signaling. The term appropriately captures the shared catalytic mechanism across activin, nodal and other ALK4-dependent ligand contexts. Reason: ACVR1B is a transmembrane serine/threonine kinase receptor activated through its GS domain and coupled to SMAD2/3 signaling. The term appropriately captures the shared catalytic mechanism across activin, nodal and other ALK4-dependent ligand contexts. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0005515 protein binding | IPI PMID:11266516 Modulation of activin signal transduction by inhibin B and i... | REMOVE | Summary: The source concerns INhBP/IGSF1 association in the activin receptor complex. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns INhBP/IGSF1 association in the activin receptor complex. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: PMID:11266516 Activin stimulates the association of InhBP and Alk4, and inhibin B, but not inhibin A, interferes with InhBP-Alk4 complex formation. |
| GO:0005515 protein binding | IPI PMID:11278302 Transforming growth factor-beta receptor-associated protein ... | REMOVE | Summary: The source concerns TRAP1/TGFBRAP1 association with inactive receptor complexes. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns TRAP1/TGFBRAP1 association with inactive receptor complexes. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:11279102 Sorting nexin 6, a novel SNX, interacts with the transformin... | REMOVE | Summary: The source concerns sorting-nexin association with TGF-beta-family receptors. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns sorting-nexin association with TGF-beta-family receptors. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:11389842 Nodal signals to Smads through Cripto-dependent and Cripto-i... | REMOVE | Summary: The source concerns receptor association in the CRIPTO-dependent nodal experiments. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns receptor association in the CRIPTO-dependent nodal experiments. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: PMID:11389842 Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. |
| GO:0005515 protein binding | IPI PMID:12052855 Dual roles of Cripto as a ligand and coreceptor in the nodal... | REMOVE | Summary: The source concerns nodal/EGF-CFC receptor-complex association. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns nodal/EGF-CFC receptor-complex association. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:12052855 Dual roles of Cripto as a ligand and coreceptor in the nodal... | REMOVE | Summary: The source concerns nodal/EGF-CFC receptor-complex association. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns nodal/EGF-CFC receptor-complex association. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:12919325 The CRIPTO/FRL-1/CRYPTIC (CFC) domain of human Cripto. Funct... | REMOVE | Summary: The source concerns the CRIPTO CFC-domain interaction. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns the CRIPTO CFC-domain interaction. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:14517293 Myostatin signals through a transforming growth factor beta-... | REMOVE | Summary: The source concerns myostatin association with a type-II/type-I receptor complex. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns myostatin association with a type-II/type-I receptor complex. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: PMID:14517293 myostatin binds the type II Ser/Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (TbetaRI), to induce phosphorylation of Smad2/Smad3 |
| GO:0005515 protein binding | IPI PMID:14966532 Lefty blocks a subset of TGFbeta signals by antagonizing EGF... | MODIFY | Summary: Association with the type-II activin receptor is part of the receptor assembly mechanism. Replace bare protein binding with type II activin receptor binding; independent ALK4/ActRIIB assembly experiments support the interaction class. Reason: Association with the type-II activin receptor is part of the receptor assembly mechanism. Replace bare protein binding with type II activin receptor binding; independent ALK4/ActRIIB assembly experiments support the interaction class. Proposed replacements: type II activin receptor binding Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005515 protein binding | IPI PMID:16720724 FKBP12 functions as an adaptor of the Smad7-Smurf1 complex o... | MODIFY | Summary: The partner is the inhibitory SMAD7. Replace bare protein binding with the existing I-SMAD-binding function; FKBP12-assisted recruitment regulates the duration of activin signaling. Reason: The partner is the inhibitory SMAD7. Replace bare protein binding with the existing I-SMAD-binding function; FKBP12-assisted recruitment regulates the duration of activin signaling. Proposed replacements: I-SMAD binding Supporting Evidence: PMID:16720724 FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. |
| GO:0005515 protein binding | IPI PMID:16720724 FKBP12 functions as an adaptor of the Smad7-Smurf1 complex o... | REMOVE | Summary: The source concerns FKBP12 binding at the regulatory receptor domain. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns FKBP12 binding at the regulatory receptor domain. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: PMID:16720724 FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. |
| GO:0005515 protein binding | IPI PMID:21791611 TSC-22 promotes transforming growth factor Ξ²-mediated cardia... | REMOVE | Summary: The source concerns TSC22D1 association in receptor regulation. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns TSC22D1 association in receptor regulation. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | REMOVE | Summary: The source concerns HSP90 client binding in a kinase-interaction survey. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns HSP90 client binding in a kinase-interaction survey. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | REMOVE | Summary: The source concerns a protein interaction in a variant-focused screening study. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Reason: The source concerns a protein interaction in a variant-focused screening study. Bare protein binding does not identify a molecular activity and is removed as uninformative, not as a rejection of the experiment. No new catalytic or developmental function is inferred from this interaction alone. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:8622651 Activation of signalling by the activin receptor complex. | MODIFY | Summary: Association with the type-II activin receptor is part of the receptor assembly mechanism. Replace bare protein binding with type II activin receptor binding; independent ALK4/ActRIIB assembly experiments support the interaction class. Reason: Association with the type-II activin receptor is part of the receptor assembly mechanism. Replace bare protein binding with type II activin receptor binding; independent ALK4/ActRIIB assembly experiments support the interaction class. Proposed replacements: type II activin receptor binding Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005515 protein binding | IPI PMID:8622651 Activation of signalling by the activin receptor complex. | MODIFY | Summary: Association with the type-II activin receptor is part of the receptor assembly mechanism. Replace bare protein binding with type II activin receptor binding; independent ALK4/ActRIIB assembly experiments support the interaction class. Reason: Association with the type-II activin receptor is part of the receptor assembly mechanism. Replace bare protein binding with type II activin receptor binding; independent ALK4/ActRIIB assembly experiments support the interaction class. Proposed replacements: type II activin receptor binding Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005515 protein binding | IPI PMID:9892009 Roles of pathway-specific and inhibitory Smads in activin re... | MODIFY | Summary: The partner is the inhibitory SMAD7. Replace bare protein binding with the existing I-SMAD-binding function; FKBP12-assisted recruitment regulates the duration of activin signaling. Reason: The partner is the inhibitory SMAD7. Replace bare protein binding with the existing I-SMAD-binding function; FKBP12-assisted recruitment regulates the duration of activin signaling. Proposed replacements: I-SMAD binding Supporting Evidence: PMID:16720724 FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. |
| GO:0005515 protein binding | IPI PMID:9892009 Roles of pathway-specific and inhibitory Smads in activin re... | MODIFY | Summary: The partner is a receptor-regulated SMAD substrate (SMAD2 or SMAD3). Replace bare binding with R-SMAD binding, supported by transient ligand-dependent receptor association. Reason: The partner is a receptor-regulated SMAD substrate (SMAD2 or SMAD3). Replace bare binding with R-SMAD binding, supported by transient ligand-dependent receptor association. Proposed replacements: R-SMAD binding Supporting Evidence: PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. |
| GO:0005515 protein binding | IPI PMID:9892009 Roles of pathway-specific and inhibitory Smads in activin re... | MODIFY | Summary: The partner is a receptor-regulated SMAD substrate (SMAD2 or SMAD3). Replace bare binding with R-SMAD binding, supported by transient ligand-dependent receptor association. Reason: The partner is a receptor-regulated SMAD substrate (SMAD2 or SMAD3). Replace bare binding with R-SMAD binding, supported by transient ligand-dependent receptor association. Proposed replacements: R-SMAD binding Supporting Evidence: PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. |
| GO:0005524 ATP binding | IDA PMID:12065756 SB-431542 is a potent and specific inhibitor of transforming... | ACCEPT | Summary: ATP binding is required for ALK4 kinase catalysis. Biochemical inhibitor experiments and the conserved protein-kinase ATP-binding sites support this activity; a kinase label alone is not used as evidence. Reason: ATP binding is required for ALK4 kinase catalysis. Biochemical inhibitor experiments and the conserved protein-kinase ATP-binding sites support this activity; a kinase label alone is not used as evidence. Supporting Evidence: PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 file:human/ACVR1B/ACVR1B-uniprot.txt FT BINDING 213..221 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is required for ALK4 kinase catalysis. Biochemical inhibitor experiments and the conserved protein-kinase ATP-binding sites support this activity; a kinase label alone is not used as evidence. Reason: ATP binding is required for ALK4 kinase catalysis. Biochemical inhibitor experiments and the conserved protein-kinase ATP-binding sites support this activity; a kinase label alone is not used as evidence. Supporting Evidence: PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 file:human/ACVR1B/ACVR1B-uniprot.txt FT BINDING 213..221 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Reason: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005886 plasma membrane | IDA PMID:9032295 Activin and inhibin have antagonistic effects on ligand-depe... | ACCEPT | Summary: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Reason: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Reason: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1181149 | ACCEPT | Summary: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Reason: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1181153 | ACCEPT | Summary: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Reason: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1549526 | ACCEPT | Summary: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Reason: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-1181349 | ACCEPT | Summary: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Reason: ALK4 forms ligand-responsive type-I/type-II receptor complexes at the plasma membrane. Cell-surface ligand cross-linking and receptor assembly studies independently support the localization, including the rows originally attached to Reactome reactions. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:12665502 Identification of a functional binding site for activin on t... | MODIFY | Summary: The receptor experiments measure activin-responsive transcriptional activation. Refine general transcription regulation to positive regulation of DNA-templated transcription; ALK4 acts through SMAD phosphorylation rather than binding DNA itself. Reason: The receptor experiments measure activin-responsive transcriptional activation. Refine general transcription regulation to positive regulation of DNA-templated transcription; ALK4 acts through SMAD phosphorylation rather than binding DNA itself. Proposed replacements: positive regulation of DNA-templated transcription Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:8622651 Activation of signalling by the activin receptor complex. | MODIFY | Summary: The receptor experiments measure activin-responsive transcriptional activation. Refine general transcription regulation to positive regulation of DNA-templated transcription; ALK4 acts through SMAD phosphorylation rather than binding DNA itself. Reason: The receptor experiments measure activin-responsive transcriptional activation. Refine general transcription regulation to positive regulation of DNA-templated transcription; ALK4 acts through SMAD phosphorylation rather than binding DNA itself. Proposed replacements: positive regulation of DNA-templated transcription Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. |
| GO:0007165 signal transduction | IDA PMID:12665502 Identification of a functional binding site for activin on t... | MODIFY | Summary: The signaling assertion can be specified as activin receptor signaling and nodal signaling, both supported for ALK4. Their receptor/cofactor requirements differ and are not interchangeable. Reason: The signaling assertion can be specified as activin receptor signaling and nodal signaling, both supported for ALK4. Their receptor/cofactor requirements differ and are not interchangeable. Proposed replacements: activin receptor signaling pathway nodal signaling pathway Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:11389842 Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. |
| GO:0007165 signal transduction | IDA PMID:8622651 Activation of signalling by the activin receptor complex. | MODIFY | Summary: The signaling assertion can be specified as activin receptor signaling and nodal signaling, both supported for ALK4. Their receptor/cofactor requirements differ and are not interchangeable. Reason: The signaling assertion can be specified as activin receptor signaling and nodal signaling, both supported for ALK4. Their receptor/cofactor requirements differ and are not interchangeable. Proposed replacements: activin receptor signaling pathway nodal signaling pathway Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:11389842 Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. |
| GO:0007178 cell surface receptor protein serine/threonine kinase signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: The broad cell-surface serine/threonine receptor pathway is refined to the established activin and nodal pathways. The early ALK cloning paper alone predicted receptor activity; subsequent functional experiments establish these pathways. Reason: The broad cell-surface serine/threonine receptor pathway is refined to the established activin and nodal pathways. The early ALK cloning paper alone predicted receptor activity; subsequent functional experiments establish these pathways. Proposed replacements: activin receptor signaling pathway nodal signaling pathway Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:11389842 Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. |
| GO:0007178 cell surface receptor protein serine/threonine kinase signaling pathway | TAS PMID:8397373 Activin receptor-like kinases: a novel subclass of cell-surf... | MODIFY | Summary: The broad cell-surface serine/threonine receptor pathway is refined to the established activin and nodal pathways. The early ALK cloning paper alone predicted receptor activity; subsequent functional experiments establish these pathways. Reason: The broad cell-surface serine/threonine receptor pathway is refined to the established activin and nodal pathways. The early ALK cloning paper alone predicted receptor activity; subsequent functional experiments establish these pathways. Proposed replacements: activin receptor signaling pathway nodal signaling pathway Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:11389842 Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. |
| GO:0007399 nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited nervous-system role is corroborated by conditional mouse Alk4 deletion and cortical somatostatin-interneuron development experiments. This is a developmental output of receptor signaling, not a direct human neural assay or a claim that every family member has identical neural functions. Reason: The inherited nervous-system role is corroborated by conditional mouse Alk4 deletion and cortical somatostatin-interneuron development experiments. This is a developmental output of receptor signaling, not a direct human neural assay or a claim that every family member has identical neural functions. Supporting Evidence: PMID:31676717 Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. |
| GO:0009986 cell surface | IDA PMID:12665502 Identification of a functional binding site for activin on t... | MODIFY | Summary: The cell-surface radioligand-binding assay is consistent with ALK4 embedded in the plasma membrane. Use the existing plasma-membrane term to specify its membrane location. Reason: The cell-surface radioligand-binding assay is consistent with ALK4 embedded in the plasma membrane. Use the existing plasma-membrane term to specify its membrane location. Proposed replacements: plasma membrane Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | MODIFY | Summary: Independent activin reporter and endogenous junB experiments establish transcriptional regulation. Replace broad gene-expression regulation with the supported positive DNA-templated transcription term; the ARBA prediction is not used as evidence for itself. Reason: Independent activin reporter and endogenous junB experiments establish transcriptional regulation. Replace broad gene-expression regulation with the supported positive DNA-templated transcription term; the ARBA prediction is not used as evidence for itself. Proposed replacements: positive regulation of DNA-templated transcription Supporting Evidence: PMID:11117535 activin administration failed to cause growth inhibition and an increase of the G1 population in these cells. PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Membrane is correct but can be specified as plasma membrane from receptor assembly and cell-surface ligand binding experiments. Reason: Membrane is correct but can be specified as plasma membrane from receptor assembly and cell-surface ligand binding experiments. Proposed replacements: plasma membrane Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0016361 activin receptor activity, type I | IBA GO_REF:0000033 | ACCEPT | Summary: This is the defining activin type-I receptor function: ALK4 joins ligand-bound type-II receptors and acts as the downstream kinase transducer. It does not require efficient activin capture by isolated ALK4, which the primary assembly study explicitly distinguishes. Reason: This is the defining activin type-I receptor function: ALK4 joins ligand-bound type-II receptors and acts as the downstream kinase transducer. It does not require efficient activin capture by isolated ALK4, which the primary assembly study explicitly distinguishes. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. |
| GO:0016361 activin receptor activity, type I | IDA PMID:9892009 Roles of pathway-specific and inhibitory Smads in activin re... | ACCEPT | Summary: This is the defining activin type-I receptor function: ALK4 joins ligand-bound type-II receptors and acts as the downstream kinase transducer. It does not require efficient activin capture by isolated ALK4, which the primary assembly study explicitly distinguishes. Reason: This is the defining activin type-I receptor function: ALK4 joins ligand-bound type-II receptors and acts as the downstream kinase transducer. It does not require efficient activin capture by isolated ALK4, which the primary assembly study explicitly distinguishes. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. |
| GO:0016361 activin receptor activity, type I | TAS PMID:8622651 Activation of signalling by the activin receptor complex. | ACCEPT | Summary: This is the defining activin type-I receptor function: ALK4 joins ligand-bound type-II receptors and acts as the downstream kinase transducer. It does not require efficient activin capture by isolated ALK4, which the primary assembly study explicitly distinguishes. Reason: This is the defining activin type-I receptor function: ALK4 joins ligand-bound type-II receptors and acts as the downstream kinase transducer. It does not require efficient activin capture by isolated ALK4, which the primary assembly study explicitly distinguishes. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. |
| GO:0017002 activin receptor activity | IDA PMID:12065756 SB-431542 is a potent and specific inhibitor of transforming... | MODIFY | Summary: Specify the type-I activin receptor activity already represented in this review. The contributes_to row remains interpreted at its weaker complex-component level: the binding experiment uses ALK4 in the presence of a type-II receptor, not autonomous high-affinity ligand capture. Reason: Specify the type-I activin receptor activity already represented in this review. The contributes_to row remains interpreted at its weaker complex-component level: the binding experiment uses ALK4 in the presence of a type-II receptor, not autonomous high-affinity ligand capture. Proposed replacements: activin receptor activity, type I Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. |
| GO:0017002 activin receptor activity | IDA PMID:12665502 Identification of a functional binding site for activin on t... | MODIFY | Summary: Specify the type-I activin receptor activity already represented in this review. The contributes_to row remains interpreted at its weaker complex-component level: the binding experiment uses ALK4 in the presence of a type-II receptor, not autonomous high-affinity ligand capture. Reason: Specify the type-I activin receptor activity already represented in this review. The contributes_to row remains interpreted at its weaker complex-component level: the binding experiment uses ALK4 in the presence of a type-II receptor, not autonomous high-affinity ligand capture. Proposed replacements: activin receptor activity, type I Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. |
| GO:0018107 peptidyl-threonine phosphorylation | IDA PMID:18039968 Ttrap is an essential modulator of Smad3-dependent Nodal sig... | UNDECIDED | Summary: The cited study examines TTRAP/Alk4 signaling with zebrafish developmental experiments. Its accessible abstract does not resolve the substrate-threonine phosphorylation assay or the receptor construct species. ALK4 kinase activity is independently established, but this precise experimental claim is left unresolved rather than inferred from the paper title. Reason: The cited study examines TTRAP/Alk4 signaling with zebrafish developmental experiments. Its accessible abstract does not resolve the substrate-threonine phosphorylation assay or the receptor construct species. ALK4 kinase activity is independently established, but this precise experimental claim is left unresolved rather than inferred from the paper title. Supporting Evidence: PMID:18039968 We identified Ttrap as a novel Alk4- and Smad3-interacting protein that controls gastrulation movements and left-right axis determination in zebrafish. |
| GO:0019838 growth factor binding | IPI PMID:14517293 Myostatin signals through a transforming growth factor beta-... | ACCEPT | Summary: The contributes_to assertion is appropriate: myostatin binds ActRIIB and forms a signaling complex with ALK4 or ALK5. Retain growth-factor binding at the receptor-complex contribution level without claiming that isolated ALK4 binds myostatin independently. Reason: The contributes_to assertion is appropriate: myostatin binds ActRIIB and forms a signaling complex with ALK4 or ALK5. Retain growth-factor binding at the receptor-complex contribution level without claiming that isolated ALK4 binds myostatin independently. Supporting Evidence: PMID:14517293 myostatin binds the type II Ser/Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (TbetaRI), to induce phosphorylation of Smad2/Smad3 |
| GO:0030279 negative regulation of ossification | IDA PMID:22155034 Bone morphogenetic protein-3b (BMP-3b) inhibits osteoblast d... | KEEP AS NON CORE | Summary: BMP-3b/GDF10 inhibits osteoblast differentiation through a SMAD2/3 response functionally facilitated by ALK4 and ActRIIA in mouse C2C12 cells. Retain this context-dependent skeletal output; the BMP name does not imply a canonical SMAD1/5/8 response, and this is not a human bone experiment. Reason: BMP-3b/GDF10 inhibits osteoblast differentiation through a SMAD2/3 response functionally facilitated by ALK4 and ActRIIA in mouse C2C12 cells. Retain this context-dependent skeletal output; the BMP name does not imply a canonical SMAD1/5/8 response, and this is not a human bone experiment. Supporting Evidence: PMID:22155034 the activity of BMP-3b was functionally facilitated by a combination of ALK-4 and ActRIIA. |
| GO:0030308 negative regulation of cell growth | IDA PMID:11117535 Truncated activin type I receptor Alk4 isoforms are dominant... | KEEP AS NON CORE | Summary: Truncated ALK4 isoforms block activin-induced growth inhibition and G1 accumulation in human K562 cells, supporting the growth-restraining role of intact receptor signaling in this context. This is a downstream cellular phenotype rather than a universal effect in every cell type. Reason: Truncated ALK4 isoforms block activin-induced growth inhibition and G1 accumulation in human K562 cells, supporting the growth-restraining role of intact receptor signaling in this context. This is a downstream cellular phenotype rather than a universal effect in every cell type. Supporting Evidence: PMID:11117535 activin administration failed to cause growth inhibition and an increase of the G1 population in these cells. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0030334 regulation of cell migration | IEA GO_REF:0000117 | MODIFY | Summary: ALK4 knockdown reduces trophoblast invasion in the full-text experiment despite the paper's ALK7-focused title. The existing positive regulation of trophoblast cell migration term specifies this supported context; no migration activity is inferred from the ARBA rule alone. Reason: ALK4 knockdown reduces trophoblast invasion in the full-text experiment despite the paper's ALK7-focused title. The existing positive regulation of trophoblast cell migration term specifies this supported context; no migration activity is inferred from the ARBA rule alone. Proposed replacements: positive regulation of trophoblast cell migration Supporting Evidence: PMID:21356369 ALK7 and Nodal siRNAs significantly increased cell invasion, whereas ALK4 siRNA had the opposite effect |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:16720724 FKBP12 functions as an adaptor of the Smad7-Smurf1 complex o... | KEEP AS NON CORE | Summary: The FKBP12-SMAD7-SMURF1 complex associates with ALK4 and controls receptor ubiquitination. Retain ubiquitin-ligase binding as a regulatory interaction, not receptor ubiquitin-ligase catalytic activity or a claim that receptor ubiquitination proves ubiquitin binding. Reason: The FKBP12-SMAD7-SMURF1 complex associates with ALK4 and controls receptor ubiquitination. Retain ubiquitin-ligase binding as a regulatory interaction, not receptor ubiquitin-ligase catalytic activity or a claim that receptor ubiquitination proves ubiquitin binding. Supporting Evidence: PMID:16720724 FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. |
| GO:0032924 activin receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Reason: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0032924 activin receptor signaling pathway | IDA PMID:12065756 SB-431542 is a potent and specific inhibitor of transforming... | ACCEPT | Summary: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Reason: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0032924 activin receptor signaling pathway | IDA PMID:9892009 Roles of pathway-specific and inhibitory Smads in activin re... | ACCEPT | Summary: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Reason: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0032924 activin receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Reason: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0032924 activin receptor signaling pathway | IMP PMID:9884026 The role of activin type I receptors in activin A-induced gr... | ACCEPT | Summary: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Reason: ALK4 is the signaling type-I kinase in the activin receptor complex and couples type-II receptor activation to SMAD2/3-dependent transcription. Receptor assembly, substrate association and inhibitor studies support this core pathway independently of transferred or automated annotations. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:12065756 We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7 |
| GO:0032927 positive regulation of activin receptor signaling pathway | IDA PMID:16720724 FKBP12 functions as an adaptor of the Smad7-Smurf1 complex o... | ACCEPT | Summary: Activated ALK4 positively transduces activin signals through its kinase activity, as shown by the ligand-independent T206D activating mutant and loss of signaling with GS-domain mutations. The attached FKBP12 study concerns inhibition and duration control, so independent receptor-activation evidence is used rather than claiming that FKBP12-SMAD7 feedback is positive. Reason: Activated ALK4 positively transduces activin signals through its kinase activity, as shown by the ligand-independent T206D activating mutant and loss of signaling with GS-domain mutations. The attached FKBP12 study concerns inhibition and duration control, so independent receptor-activation evidence is used rather than claiming that FKBP12-SMAD7 feedback is positive. Supporting Evidence: PMID:8622651 Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation PMID:16720724 FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. |
| GO:0034711 inhibin binding | IPI PMID:7890768 Inhibin antagonizes inhibition of liver cell growth by activ... | UNDECIDED | Summary: The accessible primary abstract places inhibin binding on ActRII and explicitly reports failure to assemble the ActRII-SKR2/ALK4 complex. Thus it does not provide clean evidence for direct ALK4-inhibin binding. Publisher full text could not be accessed to adjudicate the precise experimental annotation; do not infer direct binding from pathway antagonism or from association with InhBP. Reason: The accessible primary abstract places inhibin binding on ActRII and explicitly reports failure to assemble the ActRII-SKR2/ALK4 complex. Thus it does not provide clean evidence for direct ALK4-inhibin binding. Publisher full text could not be accessed to adjudicate the precise experimental annotation; do not infer direct binding from pathway antagonism or from association with InhBP. Supporting Evidence: PMID:7890768 Inhibin also binds to ActRII through its beta subunit, competes with the binding of activin to ActRII, but fails to form the ActRII.SKR2 complex. PMID:11266516 Activin stimulates the association of InhBP and Alk4, and inhibin B, but not inhibin A, interferes with InhBP-Alk4 complex formation. |
| GO:0038092 nodal signaling pathway | IGI PMID:11389842 Nodal signals to Smads through Cripto-dependent and Cripto-i... | ACCEPT | Summary: ALK4 interacts with CRIPTO through the CFC motif; this association is required for nodal binding to the ALK4/ActRIIB complex and SMAD2 activation. Nodal signaling is a genuine ALK4 function with coreceptor requirements distinct from activin. Reason: ALK4 interacts with CRIPTO through the CFC motif; this association is required for nodal binding to the ALK4/ActRIIB complex and SMAD2 activation. Nodal signaling is a genuine ALK4 function with coreceptor requirements distinct from activin. Supporting Evidence: PMID:11389842 Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. |
| GO:0043235 signaling receptor complex | IDA PMID:14517293 Myostatin signals through a transforming growth factor beta-... | MODIFY | Summary: The signaling complex contains a type-II activin receptor and ALK4. Refine the broad receptor-complex term to the existing activin receptor complex; such receptors can also be engaged by myostatin, so the complex name does not imply that every experiment used activin ligand. Reason: The signaling complex contains a type-II activin receptor and ALK4. Refine the broad receptor-complex term to the existing activin receptor complex; such receptors can also be engaged by myostatin, so the complex name does not imply that every experiment used activin ligand. Proposed replacements: activin receptor complex Supporting Evidence: PMID:14517293 myostatin binds the type II Ser/Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (TbetaRI), to induce phosphorylation of Smad2/Smad3 PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. |
| GO:0045596 negative regulation of cell differentiation | ISS GO_REF:0000024 | MODIFY | Summary: ALK4-containing receptor signaling inhibits adipogenic and osteoblast differentiation in the cited myostatin and BMP-3b model systems. Refine the general negative differentiation claim to these supported cellular contexts; do not generalize the sign to erythroid differentiation, which ALK4 promotes. Reason: ALK4-containing receptor signaling inhibits adipogenic and osteoblast differentiation in the cited myostatin and BMP-3b model systems. Refine the general negative differentiation claim to these supported cellular contexts; do not generalize the sign to erythroid differentiation, which ALK4 promotes. Proposed replacements: negative regulation of fat cell differentiation negative regulation of osteoblast differentiation Supporting Evidence: PMID:14517293 myostatin binds the type II Ser/Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (TbetaRI), to induce phosphorylation of Smad2/Smad3 PMID:22155034 the activity of BMP-3b was functionally facilitated by a combination of ALK-4 and ActRIIA. |
| GO:0045648 positive regulation of erythrocyte differentiation | IDA PMID:9032295 Activin and inhibin have antagonistic effects on ligand-depe... | KEEP AS NON CORE | Summary: Inducible activin receptor expression and ligand treatment in human K562 cells increase hemoglobin content and limit proliferation. This directly supports the erythroid differentiation response as a context-dependent biological output. Reason: Inducible activin receptor expression and ligand treatment in human K562 cells increase hemoglobin content and limit proliferation. This directly supports the erythroid differentiation response as a context-dependent biological output. Supporting Evidence: PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0046332 SMAD binding | IDA PMID:12065756 SB-431542 is a potent and specific inhibitor of transforming... | MODIFY | Summary: The signaling receptor binds R-SMAD substrates SMAD2/3 and inhibitory SMAD7. Refine broad SMAD binding to both established classes; SMAD4 is a downstream common mediator and is not inferred to be a receptor kinase substrate. Reason: The signaling receptor binds R-SMAD substrates SMAD2/3 and inhibitory SMAD7. Refine broad SMAD binding to both established classes; SMAD4 is a downstream common mediator and is not inferred to be a receptor kinase substrate. Proposed replacements: R-SMAD binding I-SMAD binding Supporting Evidence: PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. PMID:16720724 FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. |
| GO:0046777 protein autophosphorylation | IDA PMID:18039968 Ttrap is an essential modulator of Smad3-dependent Nodal sig... | ACCEPT | Summary: Autophosphorylation is supported by curated experimental receptor biochemistry in UniProt. It is distinguished from the activating transphosphorylation of the GS domain by type-II receptors. The specific experiments in the attached TTRAP paper were not independently reconstructed from its abstract. Reason: Autophosphorylation is supported by curated experimental receptor biochemistry in UniProt. It is distinguished from the activating transphosphorylation of the GS domain by type-II receptors. The specific experiments in the attached TTRAP paper were not independently reconstructed from its abstract. Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. file:human/ACVR1B/ACVR1B-uniprot.txt Autophosphorylated. |
| GO:0048179 activin receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: ALK4 assembles with activin-bound ACVR2A or ACVR2B as the type-I subunit of an activin receptor complex. Ligand cross-linking, receptor association and GS-domain activation establish this complex membership. Reason: ALK4 assembles with activin-bound ACVR2A or ACVR2B as the type-I subunit of an activin receptor complex. Ligand cross-linking, receptor association and GS-domain activation establish this complex membership. Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0048179 activin receptor complex | IDA PMID:12665502 Identification of a functional binding site for activin on t... | ACCEPT | Summary: ALK4 assembles with activin-bound ACVR2A or ACVR2B as the type-I subunit of an activin receptor complex. Ligand cross-linking, receptor association and GS-domain activation establish this complex membership. Reason: ALK4 assembles with activin-bound ACVR2A or ACVR2B as the type-I subunit of an activin receptor complex. Ligand cross-linking, receptor association and GS-domain activation establish this complex membership. Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
| GO:0048185 activin binding | IDA PMID:12665502 Identification of a functional binding site for activin on t... | ACCEPT | Summary: ALK4 contacts activin in a cooperative complex with a type-II receptor; extracellular-domain mutagenesis and radioligand cross-linking identify its contribution to the ligand-binding surface. The contributes_to row is explicitly a complex contribution. Neither row is interpreted as efficient activin binding by isolated ALK4. Reason: ALK4 contacts activin in a cooperative complex with a type-II receptor; extracellular-domain mutagenesis and radioligand cross-linking identify its contribution to the ligand-binding surface. The contributes_to row is explicitly a complex contribution. Neither row is interpreted as efficient activin binding by isolated ALK4. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. |
| GO:0048185 activin binding | IEA GO_REF:0000107 | ACCEPT | Summary: ALK4 contacts activin in a cooperative complex with a type-II receptor; extracellular-domain mutagenesis and radioligand cross-linking identify its contribution to the ligand-binding surface. The contributes_to row is explicitly a complex contribution. Neither row is interpreted as efficient activin binding by isolated ALK4. Reason: ALK4 contacts activin in a cooperative complex with a type-II receptor; extracellular-domain mutagenesis and radioligand cross-linking identify its contribution to the ligand-binding surface. The contributes_to row is explicitly a complex contribution. Neither row is interpreted as efficient activin binding by isolated ALK4. Supporting Evidence: PMID:12665502 Cross-linking studies measuring binding of 125I-activin-A to the ALK4-trunc mutants in the presence of ActRII implicated the same residues. PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. |
| GO:0051239 regulation of multicellular organismal process | IEA GO_REF:0000117 | MODIFY | Summary: The very broad regulation of organismal processes can be specified by supported erythroid differentiation, skeletal differentiation and trophoblast migration outputs already represented in this review. These context-dependent phenotypes do not define the receptor's catalytic identity. Reason: The very broad regulation of organismal processes can be specified by supported erythroid differentiation, skeletal differentiation and trophoblast migration outputs already represented in this review. These context-dependent phenotypes do not define the receptor's catalytic identity. Proposed replacements: positive regulation of erythrocyte differentiation negative regulation of ossification positive regulation of trophoblast cell migration Supporting Evidence: PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. PMID:22155034 the activity of BMP-3b was functionally facilitated by a combination of ALK-4 and ActRIIA. PMID:21356369 ALK7 and Nodal siRNAs significantly increased cell invasion, whereas ALK4 siRNA had the opposite effect |
| GO:0070411 I-SMAD binding | IPI PMID:16720724 FKBP12 functions as an adaptor of the Smad7-Smurf1 complex o... | KEEP AS NON CORE | Summary: SMAD7 associates with ALK4 in the inhibitory FKBP12-SMAD7-SMURF1 complex. This specific regulatory binding activity controls signaling duration and is separate from R-SMAD substrate recognition. Reason: SMAD7 associates with ALK4 in the inhibitory FKBP12-SMAD7-SMURF1 complex. This specific regulatory binding activity controls signaling duration and is separate from R-SMAD substrate recognition. Supporting Evidence: PMID:16720724 FKBP12 also interacted with another inhibitory molecule of activin signal, Smad7, in an activin-dependent manner, and formed a complex with Smad7 on the type I receptor. PMID:9892009 the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. |
| GO:0071363 cellular response to growth factor stimulus | IBA GO_REF:0000033 | ACCEPT | Summary: ALK4 responds to activin and nodal and participates in other TGF-beta-superfamily ligand responses with appropriate partners. Growth-factor response is valid at this shared multi-ligand level; the IBA is not treated as a pairwise transfer from its donor list. Reason: ALK4 responds to activin and nodal and participates in other TGF-beta-superfamily ligand responses with appropriate partners. Growth-factor response is valid at this shared multi-ligand level; the IBA is not treated as a pairwise transfer from its donor list. Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:11389842 Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. PMID:14517293 myostatin binds the type II Ser/Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (TbetaRI), to induce phosphorylation of Smad2/Smad3 |
| GO:0097191 extrinsic apoptotic signaling pathway | IMP PMID:9884026 The role of activin type I receptors in activin A-induced gr... | KEEP AS NON CORE | Summary: Overexpression of ActRIB enhances activin-induced apoptosis in mouse HS-72 B-cell hybridomas. Retain this ligand-triggered apoptotic output as a context-dependent mammalian inference; it does not imply that ALK4 is a caspase or an obligatory death receptor in all cells. Reason: Overexpression of ActRIB enhances activin-induced apoptosis in mouse HS-72 B-cell hybridomas. Retain this ligand-triggered apoptotic output as a context-dependent mammalian inference; it does not imply that ALK4 is a caspase or an obligatory death receptor in all cells. Supporting Evidence: PMID:9884026 HS-72 clones that over-expressed ActRIB significantly facilitated activin A-induced apoptosis. |
| GO:1901165 positive regulation of trophoblast cell migration | IDA PMID:21356369 Nodal signals through activin receptor-like kinase 7 to inhi... | KEEP AS NON CORE | Summary: The full text directly tests ALK4 siRNA: unlike ALK7 or nodal knockdown, it reduces trophoblast invasion. The authors relate this effect to loss of pro-invasive activin signaling. Retain the experimentally curated positive migration role and do not mistake the ALK7-focused title for absence of ALK4 experiments. Reason: The full text directly tests ALK4 siRNA: unlike ALK7 or nodal knockdown, it reduces trophoblast invasion. The authors relate this effect to loss of pro-invasive activin signaling. Retain the experimentally curated positive migration role and do not mistake the ALK7-focused title for absence of ALK4 experiments. Supporting Evidence: PMID:21356369 ALK7 and Nodal siRNAs significantly increased cell invasion, whereas ALK4 siRNA had the opposite effect |
| GO:1902554 serine/threonine protein kinase complex | IEA GO_REF:0000117 | MODIFY | Summary: ALK4 and its type-II receptor partners form a membrane receptor complex with serine/threonine kinase activity. Refine the general kinase-complex label to the established activin receptor complex. Reason: ALK4 and its type-II receptor partners form a membrane receptor complex with serine/threonine kinase activity. Refine the general kinase-complex label to the established activin receptor complex. Proposed replacements: activin receptor complex Supporting Evidence: PMID:8622651 Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. PMID:9032295 activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. |
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