SMAD3 is a receptor-regulated SMAD transcription factor that relays TGF-beta, activin and nodal signals from activated serine/threonine kinase receptors to the nucleus. Receptor-mediated C-terminal phosphorylation promotes SMAD complex assembly, including heteromeric complexes with SMAD4. Its MH1 domain directly recognizes regulatory DNA, while its MH2 domain mediates interactions with receptors, other SMADs and transcriptional partners. Nuclear SMAD3 activates or represses target genes according to its binding partners and cellular context; some responses occur independently of SMAD4. It regulates cell growth and differentiation, extracellular matrix production, epithelial plasticity and immune responses. SMAD3 also participates in context-dependent post-transcriptional regulation, including primary microRNA processing and stabilization of beta-catenin. It shuttles between cytoplasmic and nuclear compartments, and pathogenic variants cause a heritable aortopathy within the Loeys-Dietz syndrome spectrum.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Reason: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. PMID:9732876 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. |
| GO:0009653 anatomical structure morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SMAD3 signaling contributes to tissue morphogenesis, including skeletal development and repair. This is a context-dependent organismal output of a conserved signal transducer, not a claim that all SMAD paralogs have identical developmental roles. Reason: SMAD3 signaling contributes to tissue morphogenesis, including skeletal development and repair. This is a context-dependent organismal output of a conserved signal transducer, not a claim that all SMAD paralogs have identical developmental roles. Supporting Evidence: PMID:11585338 These findings are supported by studies with isolated primary osteoblasts that show TGF-beta can no longer inhibit the differentiation of osteoblasts in the absence of Smad3; yet, TGF-beta-stimulated proliferation remains intact. PMID:21035443 Sox9 expression clearly decreased at both mRNA and protein levels in the early stage of fracture in KO mice. |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SMAD3 regulates differentiation in several lineages; skeletal and adipocyte studies support the general biological role. The direction and phenotype depend on cell type, so a single lineage-specific replacement would lose valid scope. Reason: SMAD3 regulates differentiation in several lineages; skeletal and adipocyte studies support the general biological role. The direction and phenotype depend on cell type, so a single lineage-specific replacement would lose valid scope. Supporting Evidence: PMID:11585338 These findings are supported by studies with isolated primary osteoblasts that show TGF-beta can no longer inhibit the differentiation of osteoblasts in the absence of Smad3; yet, TGF-beta-stimulated proliferation remains intact. PMID:21035443 Sox9 expression clearly decreased at both mRNA and protein levels in the early stage of fracture in KO mice. |
| GO:0032924 activin receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD3 is an intracellular effector of activin receptors. PMID:9892009 directly examines activin receptor association, release and SMAD4 assembly. PMID:15150278, attached to some seeded rows, principally tests nodal/ALK7 signaling in human trophoblast cells; that paper alone is not ligand-specific evidence for activin. Reason: SMAD3 is an intracellular effector of activin receptors. PMID:9892009 directly examines activin receptor association, release and SMAD4 assembly. PMID:15150278, attached to some seeded rows, principally tests nodal/ALK7 signaling in human trophoblast cells; that paper alone is not ligand-specific evidence for activin. Supporting Evidence: PMID:9892009 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. PMID:12844345 Using p3TP-luc, the H295R cells show transcriptional activation of this activin-responsive reporter in the presence of activin A. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD3 is a direct DNA-binding regulator of RNA polymerase II transcription, with activation or repression depending on the promoter and associated factors. This is a core activity shared across its TGF-beta/activin responses. Reason: SMAD3 is a direct DNA-binding regulator of RNA polymerase II transcription, with activation or repression depending on the promoter and associated factors. This is a core activity shared across its TGF-beta/activin responses. Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0060395 SMAD protein signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD3 is a core component of the SMAD protein signal transduction pathway. Upon TGF-beta receptor activation, SMAD3 is phosphorylated, complexes with SMAD4, and translocates to the nucleus. IBA well-supported. Reason: Core biological process. SMAD3 is one of the principal R-SMADs mediating TGF-beta/activin signal transduction through the canonical SMAD pathway. Supporting Evidence: PMID:9311995 TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction PMID:8774881 hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex file:human/SMAD3/SMAD3-deep-research-falcon.md The MH1 domain binds short Smadβbinding elements (SBE, 5β²βGTCT/AGACβ3β²) and CAGAβbox variants, whereas MH2 mediates receptor docking, SMAD4 assembly, and cofactor recruitment |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD3 is a key intracellular mediator of TGF-beta receptor signaling. Activated by TGFBR1/ALK5 phosphorylation. IBA well-supported. Reason: Core biological process. SMAD3 is phosphorylated directly by the TGF-beta type I receptor and is essential for canonical TGF-beta signal transduction. Supporting Evidence: PMID:8774881 The activity of hMAD-3 and -4 was regulated by the TGF-beta receptors, and hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex PMID:9311995 Smad2 and Smad3 interacted with the kinase-deficient TGF-beta type I receptor |
| GO:0071144 heteromeric SMAD protein complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phosphorylated SMAD3 assembles with SMAD4 into a heteromeric signaling complex. Structural analysis establishes two phosphorylated R-SMAD subunits with one SMAD4; this does not imply that every SMAD3 response requires SMAD4. Reason: Phosphorylated SMAD3 assembles with SMAD4 into a heteromeric signaling complex. Structural analysis establishes two phosphorylated R-SMAD subunits with one SMAD4; this does not imply that every SMAD3 response requires SMAD4. Supporting Evidence: PMID:15350224 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:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD3 positively regulates transcription by RNA polymerase II at TGF-beta target gene promoters. IBA supported. Reason: Core biological process. SMAD3/SMAD4 complexes recruit p300/CBP coactivators to activate transcription of TGF-beta responsive genes. Supporting Evidence: PMID:9732876 Smad3 and Smad4 also act together with c-Jun and c-Fos to activate transcription in response to TGF-beta |
| GO:0070411 I-SMAD binding | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD7 directly associates with receptor-regulated SMADs, including SMAD3, through MH2 domains and competes with SMAD4. This specific interaction supports I-SMAD binding; receptor competition by itself would not demonstrate binding. Reason: SMAD7 directly associates with receptor-regulated SMADs, including SMAD3, through MH2 domains and competes with SMAD4. This specific interaction supports I-SMAD binding; receptor competition by itself would not demonstrate binding. Supporting Evidence: PMID:26555259 Smad7 oligomerized with R-Smad proteins upon TGF-Ξ² signaling and directly inhibited R-Smad activity, as assessed by Gal4-luciferase reporter assays. |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | MODIFY | Summary: DNA binding is established, but the existing RNA polymerase II cis-regulatory region sequence-specific DNA-binding annotation describes the demonstrated specificity more precisely. Reason: DNA binding is established, but the existing RNA polymerase II cis-regulatory region sequence-specific DNA-binding annotation describes the demonstrated specificity more precisely. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. PMID:9732876 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. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for nucleus localization. SMAD3 translocates to nucleus upon TGF-beta stimulation. Reason: Well-supported. SMAD3 is found in nucleus upon activation. Multiple IDA annotations also confirm this. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for transcription regulator complex. SMAD3 forms complexes with SMAD4 and other transcription factors. Reason: Correct. SMAD3/SMAD4 complexes function as transcription regulator complexes. Also supported by IDA (PMID:21947082). Supporting Evidence: PMID:25060702 in the presence of TTF-1, Smad3 regulates the transcription of certain genes independently of Smad4. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for cytoplasm localization. SMAD3 resides in cytoplasm when inactive. Reason: Well-supported. SMAD3 shuttles between cytoplasm and nucleus, residing primarily in cytoplasm before TGF-beta stimulation. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000120 | MODIFY | Summary: SMAD3 directly activates and represses RNA polymerase II transcription in distinct promoter contexts. Replace the general regulation term with both supported directional descendants, rather than discarding either activity. Reason: SMAD3 directly activates and represses RNA polymerase II transcription in distinct promoter contexts. Replace the general regulation term with both supported directional descendants, rather than discarding either activity. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0032502 developmental process | IEA GO_REF:0000117 | MODIFY | Summary: Developmental process is true but uninformative at this level. Existing anatomical morphogenesis and cell differentiation annotations capture supported developmental outputs more precisely. Reason: Developmental process is true but uninformative at this level. Existing anatomical morphogenesis and cell differentiation annotations capture supported developmental outputs more precisely. Proposed replacements: anatomical structure morphogenesis cell differentiation Supporting Evidence: PMID:11585338 These findings are supported by studies with isolated primary osteoblasts that show TGF-beta can no longer inhibit the differentiation of osteoblasts in the absence of Smad3; yet, TGF-beta-stimulated proliferation remains intact. PMID:21035443 Sox9 expression clearly decreased at both mRNA and protein levels in the early stage of fracture in KO mice. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: The MH1 structure identifies coordinated zinc rather than an unspecified metal; refine to the existing zinc-ion binding term. Reason: The MH1 structure identifies coordinated zinc rather than an unspecified metal; refine to the existing zinc-ion binding term. Proposed replacements: zinc ion binding Supporting Evidence: PMID:12686552 In addition, the MH1 domain is found to contain a bound zinc atom using four invariant residues among Smad proteins, three cysteines and one histidine. |
| GO:0071363 cellular response to growth factor stimulus | IEA GO_REF:0000117 | ACCEPT | Summary: SMAD3 transduces responses to several growth factors, including TGF-beta and activin; this term retains the shared multi-ligand scope rather than restricting the response to TGF-beta alone. Reason: SMAD3 transduces responses to several growth factors, including TGF-beta and activin; this term retains the shared multi-ligand scope rather than restricting the response to TGF-beta alone. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:9892009 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. |
| GO:0141091 transforming growth factor beta receptor superfamily signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: SMAD3 is a signal transducer in the TGF-beta, activin and nodal receptor pathways. Replace the superfamily-level pathway term with all three supported existing pathway terms; the distinction is ligand/receptor usage, not a generic BMP-SMAD1/5/9 assignment. Reason: SMAD3 is a signal transducer in the TGF-beta, activin and nodal receptor pathways. Replace the superfamily-level pathway term with all three supported existing pathway terms; the distinction is ligand/receptor usage, not a generic BMP-SMAD1/5/9 assignment. Proposed replacements: transforming growth factor beta receptor signaling pathway activin receptor signaling pathway nodal signaling pathway Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:9892009 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. PMID:15150278 The growth inhibitory effect of Nodal was also blocked by dominant-negative Smad2/3. |
| GO:0005515 protein binding | IPI PMID:11278756 Ski-interacting protein interacts with Smad proteins to augm... | MODIFY | Summary: The cited study supports SKIP coactivator association and modulation of TGF-beta-dependent transcription. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports SKIP coactivator association and modulation of TGF-beta-dependent transcription. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: transcription coactivator binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:11387212 The adaptor molecule Disabled-2 links the transforming growt... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:12154125 Smad3 allostery links TGF-beta receptor kinase activation to... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:12650946 Identification of three novel Smad binding proteins involved... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:12857746 Direct interaction of Ski with either Smad3 or Smad4 is nece... | MODIFY | Summary: The cited study supports direct SKI binding and repression of SMAD3-mediated transcription. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports direct SKI binding and repression of SMAD3-mediated transcription. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:14525983 DACH1 inhibits transforming growth factor-beta signaling thr... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:15084259 Integration of Smad and forkhead pathways in the control of ... | MODIFY | Summary: The cited study supports SMAD-FoxO complexes regulating p21 transcription. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports SMAD-FoxO complexes regulating p21 transcription. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:15231748 Functional proteomics mapping of a human signaling pathway. | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:15350224 Structural basis of heteromeric smad protein assembly in TGF... | MODIFY | Summary: The cited study supports structurally resolved SMAD3-SMAD4 heterotrimer assembly. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports structurally resolved SMAD3-SMAD4 heterotrimer assembly. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: co-SMAD binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:15527767 Proteomics-based identification of proteins interacting with... | MODIFY | Summary: The cited study supports SMAD3 binding to the bHLH transcription factor SREBP2. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports SMAD3 binding to the bHLH transcription factor SREBP2. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: bHLH transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:16007207 Hepatitis C virus core variants isolated from liver tumor bu... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:17785517 Msk is required for nuclear import of TGF-{beta}/BMP-activat... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:18548003 SMAD proteins control DROSHA-mediated microRNA maturation. | MODIFY | Summary: The cited study supports R-SMAD binding to DDX5/p68 in the DROSHA microprocessor. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports R-SMAD binding to DDX5/p68 in the DROSHA microprocessor. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: DEAD/H-box RNA helicase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:18729074 Identification of novel Smad2 and Smad3 associated proteins ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:19032343 Ski co-repressor complexes maintain the basal repressed stat... | MODIFY | Summary: The cited study supports SKI corepressor complexes containing SMAD3 on the SMAD7 promoter. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports SKI corepressor complexes containing SMAD3 on the SMAD7 promoter. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19135894 FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta s... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:20061380 MTMR4 attenuates transforming growth factor beta (TGFbeta) s... | MODIFY | Summary: The cited study supports MTMR4 binding to phosphorylated R-SMADs during endosomal dephosphorylation. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports MTMR4 binding to phosphorylated R-SMADs during endosomal dephosphorylation. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: protein phosphatase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:21258410 Selective targeting of activating and inhibitory Smads by di... | MODIFY | Summary: The cited study supports WWP2 ubiquitin ligase interaction with SMAD3. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports WWP2 ubiquitin ligase interaction with SMAD3. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21297662 Homeodomain protein DLX4 counteracts key transcriptional con... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:21532621 Nodal enhances the activity of FoxO3a and its synergistic in... | MODIFY | Summary: The cited study supports FoxO3a-SMAD cooperation at the cyclin G2 promoter. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports FoxO3a-SMAD cooperation at the cyclin G2 promoter. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21597466 Antagonistic regulation of EMT by TIF1Ξ³ and Smad4 in mammary... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:21828274 HEB and E2A function as SMAD/FOXH1 cofactors. | MODIFY | Summary: The cited study supports HEB/E2A bHLH transcription factor association. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports HEB/E2A bHLH transcription factor association. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: bHLH transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:22045334 Ablation of Smurf2 reveals an inhibition in TGF-Ξ² signalling... | MODIFY | Summary: The cited study supports Smurf2 interaction with SMAD3 and multiple monoubiquitination. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports Smurf2 interaction with SMAD3 and multiple monoubiquitination. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22442258 Intercellular variation in signaling through the TGF-Ξ² pathw... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:22538441 CSMD1 exhibits antitumor activity in A375 melanoma cells thr... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:25670079 14-3-3ΞΆ turns TGF-Ξ²'s function from tumor suppressor to meta... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:26680585 ShcA Protects against Epithelial-Mesenchymal Transition thro... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:28471448 MiR-1 suppresses tumor cell proliferation in colorectal canc... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:39243984 Gain-of-function variants in SMAD4 compromise respiratory ep... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0042802 identical protein binding | IPI PMID:18729074 Identification of novel Smad2 and Smad3 associated proteins ... | ACCEPT | Summary: SMAD3 self-association is supported by biochemical studies of SMAD assembly. Identical protein binding does not specify that all physiological complexes are dimers; phosphorylated R-SMADs also participate in trimers. Reason: SMAD3 self-association is supported by biochemical studies of SMAD assembly. Identical protein binding does not specify that all physiological complexes are dimers; phosphorylated R-SMADs also participate in trimers. Supporting Evidence: PMID:9111321 We now show that Smad3 and Smad4 associate in homomeric and heteromeric interactions, as assessed by yeast two-hybrid and coimmunoprecipitation analyses. PMID:15350224 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. |
| GO:0042802 identical protein binding | IPI PMID:22045334 Ablation of Smurf2 reveals an inhibition in TGF-Ξ² signalling... | ACCEPT | Summary: SMAD3 self-association is supported by biochemical studies of SMAD assembly. Identical protein binding does not specify that all physiological complexes are dimers; phosphorylated R-SMADs also participate in trimers. Reason: SMAD3 self-association is supported by biochemical studies of SMAD assembly. Identical protein binding does not specify that all physiological complexes are dimers; phosphorylated R-SMADs also participate in trimers. Supporting Evidence: PMID:9111321 We now show that Smad3 and Smad4 associate in homomeric and heteromeric interactions, as assessed by yeast two-hybrid and coimmunoprecipitation analyses. PMID:15350224 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. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for negative regulation of Pol II transcription. SMAD3 can also repress transcription at certain loci. Reason: SMAD3 acts as both transcriptional activator and repressor depending on context and cofactors (Ski/SnoN, TGIF). Also supported by IDA (PMID:28467929). Supporting Evidence: PMID:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0000165 MAPK cascade | IEA GO_REF:0000107 | UNDECIDED | Summary: The donor study establishes SMAD3-dependent IL23A transcription alongside MAPK-dependent ATF2 activation. Its accessible abstract does not show that SMAD3 itself executes a MAPK-cascade step; full mechanistic resolution of this transfer is needed. This is not a rejection based on the lack of a human assay. Reason: The donor study establishes SMAD3-dependent IL23A transcription alongside MAPK-dependent ATF2 activation. Its accessible abstract does not show that SMAD3 itself executes a MAPK-cascade step; full mechanistic resolution of this transfer is needed. This is not a rejection based on the lack of a human assay. Supporting Evidence: PMID:18802055 Chromosomal DNA immunoprecipitation assays revealed that SMAD-3 and ATF-2 bind to the endogenous p19 promoter in RAW264.7 cells and SJL/J SPM following challenge with TMEV. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (Ensembl/UniProt) for RNA polymerase II transcription regulatory region sequence-specific DNA binding. Reason: Correct. SMAD3 binds SBE sequences in Pol II regulatory regions. Also supported by IDA annotations. Supporting Evidence: PMID:9732876 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. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for DNA-binding transcription activator activity, Pol II-specific. Reason: Correct. SMAD3 activates Pol II transcription at TGF-beta target genes. Also supported by multiple IDA annotations. Supporting Evidence: PMID:9732876 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. |
| GO:0001649 osteoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Smad3-null mice and isolated osteoblasts show altered differentiation, osteocyte fate and bone formation. This supports the ortholog-transferred osteoblast role as non-core; it is not a direct human experiment. Reason: Smad3-null mice and isolated osteoblasts show altered differentiation, osteocyte fate and bone formation. This supports the ortholog-transferred osteoblast role as non-core; it is not a direct human experiment. Supporting Evidence: PMID:11585338 These findings are supported by studies with isolated primary osteoblasts that show TGF-beta can no longer inhibit the differentiation of osteoblasts in the absence of Smad3; yet, TGF-beta-stimulated proliferation remains intact. |
| GO:0001657 ureteric bud development | IEA GO_REF:0000107 | UNDECIDED | Summary: The accessible donor study describes Smad expression during mouse kidney development and proposes developmental roles. It does not establish the specific contribution of SMAD3 to ureteric bud development; full-text verification is needed before judging this transfer. Reason: The accessible donor study describes Smad expression during mouse kidney development and proposes developmental roles. It does not establish the specific contribution of SMAD3 to ureteric bud development; full-text verification is needed before judging this transfer. Supporting Evidence: PMID:14656760 Based on the observed patterns of expression, we speculate that individual or combinations of Smads may play specific roles in cell-fate determination during kidney development. |
| GO:0001836 release of cytochrome c from mitochondria | IEA GO_REF:0000107 | UNDECIDED | Summary: The donor study establishes Smad3-dependent BAD cleavage and apoptosis in rat FaO cells, but the accessible abstract does not resolve the particular cytochrome-c release experiment. Retain uncertainty rather than rejecting a likely downstream apoptotic mechanism from an incomplete source. Reason: The donor study establishes Smad3-dependent BAD cleavage and apoptosis in rat FaO cells, but the accessible abstract does not resolve the particular cytochrome-c release experiment. Retain uncertainty rather than rejecting a likely downstream apoptotic mechanism from an incomplete source. Supporting Evidence: PMID:11839804 Overexpression of Smad3 dramatically enhanced TGF-beta 1-induced cleavage of BAD and apoptosis, whereas antisense Smad3 blocked TGF-beta 1-induced apoptosis and BAD cleavage. |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for chromatin binding from mouse data. Reason: Correct. SMAD3 binds chromatin at enhancer/promoter regions. Also supported by IDA chromatin localization (PMID:21828274). Supporting Evidence: |
| GO:0003690 double-stranded DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: The structural and promoter evidence supports sequence-specific binding to regulatory double-stranded DNA; refine to the existing RNA polymerase II cis-regulatory region term. Reason: The structural and promoter evidence supports sequence-specific binding to regulatory double-stranded DNA; refine to the existing RNA polymerase II cis-regulatory region term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. PMID:9732876 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. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | MODIFY | Summary: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Reason: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0005518 collagen binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The study reports collagen I, III and V interactions with SMAD3 MH2 and weaker binding to full-length SMAD3 by yeast two-hybrid and GST pull-down assays. This is actual binding evidence, not merely regulation of collagen gene expression. Retain as an experimentally motivated, context-dependent interaction without implying that SMAD3 is normally an extracellular collagen receptor. Reason: The study reports collagen I, III and V interactions with SMAD3 MH2 and weaker binding to full-length SMAD3 by yeast two-hybrid and GST pull-down assays. This is actual binding evidence, not merely regulation of collagen gene expression. Retain as an experimentally motivated, context-dependent interaction without implying that SMAD3 is normally an extracellular collagen receptor. Supporting Evidence: PMID:14559231 Each collagen also bound to the MH2 domains of Smads 4 and 7 and, to a lesser extent, full-length Smads 1, 2, 3, and 4. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for plasma membrane localization from mouse data. Reason: SMAD3 can associate with TGF-beta receptors at the plasma membrane during initial activation, but its primary functional locations are cytoplasm and nucleus. Plasma membrane localization is transient. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for TGF-beta receptor signaling pathway from rat orthologs. Reason: Correct. Core biological process for SMAD3. Also supported by multiple IDA and IMP annotations. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0007254 JNK cascade | IEA GO_REF:0000107 | UNDECIDED | Summary: The donor abstract assigns JNK-dependent activation to ATF2 while SMAD3 mediates a parallel transcriptional input. The specific evidence that places SMAD3 in the JNK cascade could not be verified from the accessible source. Reason: The donor abstract assigns JNK-dependent activation to ATF2 while SMAD3 mediates a parallel transcriptional input. The specific evidence that places SMAD3 in the JNK cascade could not be verified from the accessible source. Supporting Evidence: PMID:18802055 Chromosomal DNA immunoprecipitation assays revealed that SMAD-3 and ATF-2 bind to the endogenous p19 promoter in RAW264.7 cells and SJL/J SPM following challenge with TMEV. |
| GO:0008013 beta-catenin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SMAD3 interacts with beta-catenin in chondrocyte models; mapped interactions and complex assembly support a context-dependent beta-catenin-binding function. The donor study is not presented as a direct human assay. Reason: SMAD3 interacts with beta-catenin in chondrocyte models; mapped interactions and complex assembly support a context-dependent beta-catenin-binding function. The donor study is not presented as a direct human assay. Supporting Evidence: PMID:20097766 Both Smad3 and Smad4 were required for the interaction with beta-catenin and protected beta-catenin from an ubiquitin-proteasome-dependent degradation. |
| GO:0008285 negative regulation of cell population proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for negative regulation of cell population proliferation from rat data. Reason: Valid downstream effect. TGF-beta/SMAD3 signaling inhibits cell proliferation through transcriptional regulation of CDK inhibitors (p15, p21). Also supported by IMP (PMID:14555988). Non-core pleiotropic process. Supporting Evidence: |
| GO:0010332 response to gamma radiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat radiation study reports increased SMAD3 abundance and pathway markers after radiation and their reduction with treatment. The accessible evidence does not distinguish a functional SMAD3 contribution to radiation response from an expression response; the precise transfer remains unresolved. Reason: The rat radiation study reports increased SMAD3 abundance and pathway markers after radiation and their reduction with treatment. The accessible evidence does not distinguish a functional SMAD3 contribution to radiation response from an expression response; the precise transfer remains unresolved. Supporting Evidence: PMID:34036875 Radiation exposure resulted in a significant increase (p < 0.05) in pulmonary Transforming growth factor-beta 1 (TGF-Ξ²), SMAD family member 3 (Smad3), Platelet-derived growth factor (PDGF), malondialdehyde (MDA), Total nitrate/nitrite (NO), interleukin 1Ξ² (IL-1Ξ²) and interleukin 6 (IL-6) compared to the control group. |
| GO:0010467 gene expression | IEA GO_REF:0000107 | MODIFY | Summary: The donor study concerns SMAD3-dependent regulation of profibrotic gene expression. Refine the general gene-expression assertion to SMAD3 regulation of RNA polymerase II transcription, with activation and repression supported independently; this is a correction to the regulatory role rather than a claim that regulation is an is_a child of gene expression. Reason: The donor study concerns SMAD3-dependent regulation of profibrotic gene expression. Refine the general gene-expression assertion to SMAD3 regulation of RNA polymerase II transcription, with activation and repression supported independently; this is a correction to the regulatory role rather than a claim that regulation is an is_a child of gene expression. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0019899 enzyme binding | IEA GO_REF:0000107 | MODIFY | Summary: SMAD3 binds specific enzyme classes: serine/threonine kinases, protein phosphatases and ubiquitin-protein ligases. Use these supported binding terms instead of the uninformative enzyme-binding label; none implies that SMAD3 catalyzes the enzymes' reactions. Reason: SMAD3 binds specific enzyme classes: serine/threonine kinases, protein phosphatases and ubiquitin-protein ligases. Use these supported binding terms instead of the uninformative enzyme-binding label; none implies that SMAD3 catalyzes the enzymes' reactions. Proposed replacements: protein serine/threonine kinase binding protein phosphatase binding ubiquitin protein ligase binding Supporting Evidence: PMID:16751101 This work demonstrates that PPM1A/PP2Calpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFbeta signaling. PMID:15781469 Finally, we demonstrated that CHIP served as a U-box dependent E3 ligase that can directly mediate ubiquitination and degradation of Smad3 and that this action of CHIP was independent of TGF-beta signaling. PMID:20061380 Co-immunoprecipitation experiments showed that endogenous MTMR4 interacts with phosphorylated R-Smads, and that this interaction is correlated with dephosphorylation of R-Smads. |
| GO:0023019 signal transduction involved in regulation of gene expression | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for signal transduction involved in regulation of gene expression from rat data. Reason: Correct description of SMAD3 core function: signal transduction (TGF-beta pathway) that directly regulates gene expression. Supporting Evidence: PMID:9732876 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. |
| GO:0030325 adrenal gland development | IEA GO_REF:0000107 | UNDECIDED | Summary: The study demonstrates functional activin signaling in fetal rat adrenal tissue and human H295R cells. The accessible evidence does not establish a specific SMAD3 requirement in adrenal gland development, so the narrower developmental claim remains unresolved. Reason: The study demonstrates functional activin signaling in fetal rat adrenal tissue and human H295R cells. The accessible evidence does not establish a specific SMAD3 requirement in adrenal gland development, so the narrower developmental claim remains unresolved. Supporting Evidence: PMID:12844345 Using p3TP-luc, the H295R cells show transcriptional activation of this activin-responsive reporter in the presence of activin A. |
| GO:0030335 positive regulation of cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SMAD3 linker-phosphorylation mutants alter the invasive program in Ras-transformed cells. This supports a context-dependent migration output, not a universal pro-migratory effect of SMAD3. Reason: SMAD3 linker-phosphorylation mutants alter the invasive program in Ras-transformed cells. This supports a context-dependent migration output, not a universal pro-migratory effect of SMAD3. Supporting Evidence: PMID:17545585 Conversely, selective blockade of linker phosphorylation by a mutant Smad3 lacking JNK-dependent phosphorylation sites results in preserved tumor-suppressive function via pSmad3C in Ras-transformed cells while eliminating pSmad2/3L-mediated invasive capacity. |
| GO:0030501 positive regulation of bone mineralization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Smad3 overexpression increases alkaline phosphatase activity and mineralization in mouse MC3T3-E1 osteoblasts, although TGF-beta treatment has different effects in that model. Retain the specific ortholog-supported phenotype without generalizing its sign to all bone contexts. Reason: Smad3 overexpression increases alkaline phosphatase activity and mineralization in mouse MC3T3-E1 osteoblasts, although TGF-beta treatment has different effects in that model. Retain the specific ortholog-supported phenotype without generalizing its sign to all bone contexts. Supporting Evidence: PMID:12096832 On the other hand, Smad3 greatly enhanced ALP activity and mineralization of MC3T3-E1 cells compared with empty vector, although TGF-beta inhibited ALP activity and mineralization of wild-type MC3T3-E1 cells. |
| GO:0031490 chromatin DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for chromatin DNA binding from mouse data. Reason: Correct. SMAD3 binds DNA within chromatin context at enhancers and promoters. Supported by ChIP studies. Supporting Evidence: |
| GO:0032332 positive regulation of chondrocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Smad3-null mice show reduced cartilage callus and Sox9 expression during fracture repair, supporting a chondrogenic role in that setting. This is a mammalian ortholog inference, not a human fracture assay. Reason: Smad3-null mice show reduced cartilage callus and Sox9 expression during fracture repair, supporting a chondrogenic role in that setting. This is a mammalian ortholog inference, not a human fracture assay. Supporting Evidence: PMID:21035443 Sox9 expression clearly decreased at both mRNA and protein levels in the early stage of fracture in KO mice. |
| GO:0032731 positive regulation of interleukin-1 beta production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: In rat pancreatic stellate cells, dominant-negative Smad2/3 suppresses IL-1beta expression and secretion, and Smad3 but not Smad2 restores them. Retain this specific inflammatory feedback output as non-core; it need not have the same sign as SMAD3-dependent anti-inflammatory responses in other cells. Reason: In rat pancreatic stellate cells, dominant-negative Smad2/3 suppresses IL-1beta expression and secretion, and Smad3 but not Smad2 restores them. Retain this specific inflammatory feedback output as non-core; it need not have the same sign as SMAD3-dependent anti-inflammatory responses in other cells. Supporting Evidence: PMID:16371439 Coexpression of Smad3 with dnSmad2/3 restored IL-1beta expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. |
| GO:0032916 positive regulation of transforming growth factor beta3 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Promoter occupancy, reporter mutation and Smad3 RNA interference establish TGF-beta-induced TGFB3 transcription and production. This is a direct transcriptional feedback function, not a speculative cytokine-production consequence. Reason: Promoter occupancy, reporter mutation and Smad3 RNA interference establish TGF-beta-induced TGFB3 transcription and production. This is a direct transcriptional feedback function, not a speculative cytokine-production consequence. Supporting Evidence: PMID:16891311 Small interfering RNA-CREB1 and small interfering RNA-Smad3 significantly inhibited TGFbeta stimulation of TGFbeta3 promoter reporter activity and TGFbeta3 production. |
| GO:0032993 protein-DNA complex | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for protein-DNA complex from mouse data. Reason: Correct. SMAD3 forms protein-DNA complexes at SBE-containing regulatory regions. Crystal structure of SMAD3 MH1-DNA complex solved (PMID:12686552). Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. |
| GO:0033689 negative regulation of osteoblast proliferation | IEA GO_REF:0000107 | UNDECIDED | Summary: The mouse fracture-healing study supports altered osteogenesis and chondrogenesis but its accessible abstract does not resolve the specific osteoblast proliferation assay. Do not substitute differentiation for proliferation or reject the curator from incomplete text. Reason: The mouse fracture-healing study supports altered osteogenesis and chondrogenesis but its accessible abstract does not resolve the specific osteoblast proliferation assay. Do not substitute differentiation for proliferation or reject the curator from incomplete text. Supporting Evidence: PMID:21035443 Sox9 expression clearly decreased at both mRNA and protein levels in the early stage of fracture in KO mice. |
| GO:0036120 cellular response to platelet-derived growth factor stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat VSMC study measures SMAD3 activation during PDGF-BB stimulation and drug treatment, but the accessible evidence does not resolve whether SMAD3 is mechanistically required for that response. A response term does not require SMAD3 to be a direct PDGF receptor; the uncertainty concerns the actual experiment. Reason: The rat VSMC study measures SMAD3 activation during PDGF-BB stimulation and drug treatment, but the accessible evidence does not resolve whether SMAD3 is mechanistically required for that response. A response term does not require SMAD3 to be a direct PDGF receptor; the uncertainty concerns the actual experiment. Supporting Evidence: |
| GO:0042110 T cell activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Smad3 mutant mouse T cells show altered activation and loss of TGF-beta growth inhibition. This supports the ortholog-transferred immune-cell activation role as a context-dependent output. Reason: Smad3 mutant mouse T cells show altered activation and loss of TGF-beta growth inhibition. This supports the ortholog-transferred immune-cell activation role as a context-dependent output. Supporting Evidence: PMID:10064594 Mutant T cells exhibit an activated phenotype in vivo, and are not inhibited by TGF-beta1 in vitro. |
| GO:0042177 negative regulation of protein catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The SMAD3-SMAD4-beta-catenin complex protects beta-catenin from ubiquitin-proteasome degradation. Thus negative regulation of protein catabolism is supported for a specific substrate rather than inferred from general transcriptional effects. Reason: The SMAD3-SMAD4-beta-catenin complex protects beta-catenin from ubiquitin-proteasome degradation. Thus negative regulation of protein catabolism is supported for a specific substrate rather than inferred from general transcriptional effects. Supporting Evidence: PMID:20097766 Both Smad3 and Smad4 were required for the interaction with beta-catenin and protected beta-catenin from an ubiquitin-proteasome-dependent degradation. |
| GO:0042220 response to cocaine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat nucleus accumbens studies manipulate activin/Smad3 signaling and alter cocaine-seeking behavior and neuronal plasticity. Retain this ortholog-supported response as non-core; SMAD3 need not bind cocaine directly to participate in the cellular response. Reason: Rat nucleus accumbens studies manipulate activin/Smad3 signaling and alter cocaine-seeking behavior and neuronal plasticity. Retain this ortholog-supported response as non-core; SMAD3 need not bind cocaine directly to participate in the cellular response. Supporting Evidence: PMID:26030849 Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: SMAD3 self-association is supported by biochemical studies of SMAD assembly. Identical protein binding does not specify that all physiological complexes are dimers; phosphorylated R-SMADs also participate in trimers. Reason: SMAD3 self-association is supported by biochemical studies of SMAD assembly. Identical protein binding does not specify that all physiological complexes are dimers; phosphorylated R-SMADs also participate in trimers. Supporting Evidence: PMID:9111321 We now show that Smad3 and Smad4 associate in homomeric and heteromeric interactions, as assessed by yeast two-hybrid and coimmunoprecipitation analyses. PMID:15350224 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. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Smad3 expression and a dominant-negative construct establish an anti-apoptotic PTH-Smad3 response in osteoblastic models. This context-specific protective effect coexists with pro-apoptotic SMAD3 responses elsewhere. Reason: Smad3 expression and a dominant-negative construct establish an anti-apoptotic PTH-Smad3 response in osteoblastic models. This context-specific protective effect coexists with pro-apoptotic SMAD3 responses elsewhere. Supporting Evidence: PMID:14517210 Moreover, a dominant negative mutant, Smad3DeltaC, abrogated PTH-induced anti-apoptotic effects. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: The established sequence-specific DNA-binding activity is at transcriptional regulatory elements; refine to the existing RNA polymerase II cis-regulatory region term. Reason: The established sequence-specific DNA-binding activity is at transcriptional regulatory elements; refine to the existing RNA polymerase II cis-regulatory region term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:9732876 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. |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for positive regulation of nitric oxide biosynthesis from rat data. Reason: Context-dependent downstream effect. TGF-beta/SMAD3 can regulate iNOS expression in certain cell types. Also supported by IDA (PMID:27038547). Non-core process. Supporting Evidence: PMID:27038547 Mechanism analyses revealed that the downregulation of NO and the upregulation of Ca(2+) caused by miR-199a-5p were all reversed by Smad3 overexpression in HPASMCs and HPAECs. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for positive regulation of Pol II transcription from rat data. Reason: Correct. SMAD3 activates Pol II transcription. Also supported by IBA and IMP annotations. Supporting Evidence: PMID:9732876 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. |
| GO:0050728 negative regulation of inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for negative regulation of inflammatory response from mouse data. Reason: Valid downstream effect. TGF-beta/SMAD3 is a key anti-inflammatory pathway. Also supported by NAS (ComplexPortal). Non-core immune process. Supporting Evidence: |
| GO:0050776 regulation of immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SMAD3-dependent signaling regulates immune responses in lymphocytes and inflammatory-cell contexts. Reason: Smad3-mutant mouse lymphocytes and functional IL-37 studies establish immunoregulatory outputs. Retain the context-dependent immune process without implying that every SMAD paralog has the same role. Supporting Evidence: PMID:10064594 Mutant T cells exhibit an activated phenotype in vivo, and are not inhibited by TGF-beta1 in vitro. |
| GO:0050821 protein stabilization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SMAD3 and SMAD4 protect bound beta-catenin from proteasomal degradation and facilitate its nuclear translocation. This directly supports protein stabilization as a secondary SMAD3 function. Reason: SMAD3 and SMAD4 protect bound beta-catenin from proteasomal degradation and facilitate its nuclear translocation. This directly supports protein stabilization as a secondary SMAD3 function. Supporting Evidence: PMID:20097766 Both Smad3 and Smad4 were required for the interaction with beta-catenin and protected beta-catenin from an ubiquitin-proteasome-dependent degradation. |
| GO:0050927 positive regulation of positive chemotaxis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Smad3-overexpressing primary rat hepatic stellate cells show increased chemotaxis; the study contrasts Smad2 and dominant-negative constructs. Retain this ortholog-supported stellate-cell response as non-core. Reason: Smad3-overexpressing primary rat hepatic stellate cells show increased chemotaxis; the study contrasts Smad2 and dominant-negative constructs. Retain this ortholog-supported stellate-cell response as non-core. Supporting Evidence: PMID:15987742 Smad3-overexpressing cells exhibited increased deposition of fibronectin and type 1 collagen, increased chemotaxis, and decreased proliferation compared with uninfected cells and those infected with Smad2 or either dominant negative, demonstrating different biological functions for the two Smads. |
| GO:0051496 positive regulation of stress fiber assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Primary rat hepatic stellate cells expressing Smad3 display increased alpha-smooth-muscle-actin organization in stress fibers without a corresponding increase in total alpha-SMA expression. This supports regulation of cytoskeletal organization, not actin-binding or structural activity by SMAD3. Reason: Primary rat hepatic stellate cells expressing Smad3 display increased alpha-smooth-muscle-actin organization in stress fibers without a corresponding increase in total alpha-SMA expression. This supports regulation of cytoskeletal organization, not actin-binding or structural activity by SMAD3. Supporting Evidence: PMID:15987742 Smad3-overexpressing cells exhibited increased deposition of fibronectin and type 1 collagen, increased chemotaxis, and decreased proliferation compared with uninfected cells and those infected with Smad2 or either dominant negative, demonstrating different biological functions for the two Smads. |
| GO:0051881 regulation of mitochondrial membrane potential | IEA GO_REF:0000107 | UNDECIDED | Summary: The accessible donor abstract establishes Smad3-dependent apoptosis and BAD cleavage in rat FaO cells but does not resolve the mitochondrial-potential assay. The specific transferred claim remains uncertain pending full-text verification. Reason: The accessible donor abstract establishes Smad3-dependent apoptosis and BAD cleavage in rat FaO cells but does not resolve the mitochondrial-potential assay. The specific transferred claim remains uncertain pending full-text verification. Supporting Evidence: PMID:11839804 Overexpression of Smad3 dramatically enhanced TGF-beta 1-induced cleavage of BAD and apoptosis, whereas antisense Smad3 blocked TGF-beta 1-induced apoptosis and BAD cleavage. |
| GO:0051894 positive regulation of focal adhesion assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Smad3 overexpression in primary rat hepatic stellate cells increases focal adhesions as part of myofibroblast maturation. This supports a context-dependent regulatory phenotype, not localization of SMAD3 as a focal-adhesion structural component. Reason: Smad3 overexpression in primary rat hepatic stellate cells increases focal adhesions as part of myofibroblast maturation. This supports a context-dependent regulatory phenotype, not localization of SMAD3 as a focal-adhesion structural component. Supporting Evidence: PMID:15987742 Smad3-overexpressing cells exhibited increased deposition of fibronectin and type 1 collagen, increased chemotaxis, and decreased proliferation compared with uninfected cells and those infected with Smad2 or either dominant negative, demonstrating different biological functions for the two Smads. |
| GO:0060290 transdifferentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The study supports Smad3-dependent morphological and functional maturation of primary rat hepatic stellate cells into fibrogenic myofibroblasts. Retain the transferred transdifferentiation output as non-core. Reason: The study supports Smad3-dependent morphological and functional maturation of primary rat hepatic stellate cells into fibrogenic myofibroblasts. Retain the transferred transdifferentiation output as non-core. Supporting Evidence: PMID:15987742 Smad3-overexpressing cells exhibited increased deposition of fibronectin and type 1 collagen, increased chemotaxis, and decreased proliferation compared with uninfected cells and those infected with Smad2 or either dominant negative, demonstrating different biological functions for the two Smads. |
| GO:0060395 SMAD protein signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for SMAD protein signal transduction from rat data. Reason: Correct. Core biological process. Also supported by multiple IBA and IDA annotations. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0061001 regulation of dendritic spine morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Genetic and pharmacological manipulation of activin/Smad3 signaling regulates neuronal morphological plasticity in the rat nucleus accumbens after cocaine exposure. Retain the transferred dendritic-spine regulatory role in this context, rather than asserting a universal developmental function. Reason: Genetic and pharmacological manipulation of activin/Smad3 signaling regulates neuronal morphological plasticity in the rat nucleus accumbens after cocaine exposure. Retain the transferred dendritic-spine regulatory role in this context, rather than asserting a universal developmental function. Supporting Evidence: PMID:26030849 Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. |
| GO:0061045 negative regulation of wound healing | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for negative regulation of wound healing from mouse data. Reason: Valid downstream effect. UniProt notes SMAD3 has inhibitory effect on wound healing. Non-core tissue-specific process. Supporting Evidence: PMID:21035443 Sox9 expression clearly decreased at both mRNA and protein levels in the early stage of fracture in KO mice. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for RNA polymerase II-specific DNA-binding TF binding from mouse data. Reason: Correct. SMAD3 binds other Pol II TFs (c-Jun, c-Fos, FOXH1, etc.). Also supported by IPI annotations. Supporting Evidence: PMID:9732876 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. |
| GO:0061767 negative regulation of lung blood pressure | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The miR-199a-5p/SMAD3 study connects SMAD3-dependent signaling to pulmonary hypertension phenotypes in rats and nitric-oxide/calcium responses in human pulmonary vascular cells. Retain the physiological blood-pressure outcome as a non-core mammalian inference, not a direct human blood-pressure assay. Reason: The miR-199a-5p/SMAD3 study connects SMAD3-dependent signaling to pulmonary hypertension phenotypes in rats and nitric-oxide/calcium responses in human pulmonary vascular cells. Retain the physiological blood-pressure outcome as a non-core mammalian inference, not a direct human blood-pressure assay. Supporting Evidence: PMID:27038547 Mechanism analyses revealed that the downregulation of NO and the upregulation of Ca(2+) caused by miR-199a-5p were all reversed by Smad3 overexpression in HPASMCs and HPAECs. |
| GO:0071333 cellular response to glucose stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: The cached study concerns high-glucose-associated TGF-beta/SMAD signaling in rat tubular cells. The accessible evidence does not resolve the SMAD3-specific contribution to this response; lack of direct glucose sensing is not grounds for rejecting a response annotation. Reason: The cached study concerns high-glucose-associated TGF-beta/SMAD signaling in rat tubular cells. The accessible evidence does not resolve the SMAD3-specific contribution to this response; lack of direct glucose sensing is not grounds for rejecting a response annotation. Supporting Evidence: |
| GO:0071560 cellular response to transforming growth factor beta stimulus | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for cellular response to TGF-beta stimulus from rat data. Reason: Correct. Core biological process. SMAD3 is a primary mediator of cellular responses to TGF-beta. Also supported by IDA (PMID:12902338). Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SMAD3 stabilizes beta-catenin, promotes its nuclear accumulation and increases downstream target activity in chondrocyte models. This supports positive regulation of canonical Wnt signaling; regulatory cross-talk is a valid function and does not imply that SMAD3 is a Wnt receptor. Reason: SMAD3 stabilizes beta-catenin, promotes its nuclear accumulation and increases downstream target activity in chondrocyte models. This supports positive regulation of canonical Wnt signaling; regulatory cross-talk is a valid function and does not imply that SMAD3 is a Wnt receptor. Supporting Evidence: PMID:20097766 Both Smad3 and Smad4 were required for the interaction with beta-catenin and protected beta-catenin from an ubiquitin-proteasome-dependent degradation. |
| GO:0097191 extrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for extrinsic apoptotic signaling pathway from rat data. Reason: Valid downstream effect. TGF-beta can trigger apoptosis through SMAD3-dependent transcriptional programs. Also supported by IMP (PMID:15334054). Non-core process. Supporting Evidence: |
| GO:0097305 response to alcohol | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat hippocampal RNA-sequencing study reports reduced Smad3 expression after chronic alcohol exposure. The accessible evidence does not distinguish participation in the response from being a transcriptionally responsive marker; retain uncertainty rather than calling an ortholog transfer false. Reason: The rat hippocampal RNA-sequencing study reports reduced Smad3 expression after chronic alcohol exposure. The accessible evidence does not distinguish participation in the response from being a transcriptionally responsive marker; retain uncertainty rather than calling an ortholog transfer false. Supporting Evidence: PMID:31628824 On the other hand, genes (Smad3 and Plk5) involved in negative regulation of cell proliferation were down-regulated in the hippocampus by chronic alcohol administration. |
| GO:0098586 cellular response to virus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse macrophage experiments show virus-induced TGF-beta/SMAD3 activation and SMAD3-dependent IL23A promoter occupancy and expression. This independently supports the ortholog-transferred cellular viral-response role without inferring it merely from viral-protein binding. Reason: Mouse macrophage experiments show virus-induced TGF-beta/SMAD3 activation and SMAD3-dependent IL23A promoter occupancy and expression. This independently supports the ortholog-transferred cellular viral-response role without inferring it merely from viral-protein binding. Supporting Evidence: PMID:18802055 Chromosomal DNA immunoprecipitation assays revealed that SMAD-3 and ATF-2 bind to the endogenous p19 promoter in RAW264.7 cells and SJL/J SPM following challenge with TMEV. |
| GO:1903243 negative regulation of cardiac muscle hypertrophy in response to stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The pulmonary-hypertension study implicates the miR-199a-5p/SMAD3 axis in associated cardiac hypertrophy in rats. Retain this context-specific ortholog-supported stress phenotype, not a general claim that SMAD3 always prevents cardiac hypertrophy. Reason: The pulmonary-hypertension study implicates the miR-199a-5p/SMAD3 axis in associated cardiac hypertrophy in rats. Retain this context-specific ortholog-supported stress phenotype, not a general claim that SMAD3 always prevents cardiac hypertrophy. Supporting Evidence: PMID:27038547 Mechanism analyses revealed that the downregulation of NO and the upregulation of Ca(2+) caused by miR-199a-5p were all reversed by Smad3 overexpression in HPASMCs and HPAECs. |
| GO:1990841 promoter-specific chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for promoter-specific chromatin binding from mouse data. Reason: Correct. SMAD3 binds chromatin at specific promoters of TGF-beta target genes. Supporting Evidence: PMID:18802055 Chromosomal DNA immunoprecipitation assays revealed that SMAD-3 and ATF-2 bind to the endogenous p19 promoter in RAW264.7 cells and SJL/J SPM following challenge with TMEV. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasm localization (GO_REF:0000052). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. Supporting Evidence: PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:35359452 The Interplay Between TGF-Ξ² Signaling and Cell Metabolism. | MODIFY | Summary: SMAD3 directly activates and represses RNA polymerase II transcription in distinct promoter contexts. Replace the general regulation term with both supported directional descendants, rather than discarding either activity. Reason: SMAD3 directly activates and represses RNA polymerase II transcription in distinct promoter contexts. Replace the general regulation term with both supported directional descendants, rather than discarding either activity. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0007179 transforming growth factor beta receptor signaling pathway | NAS PMID:35359452 The Interplay Between TGF-Ξ² Signaling and Cell Metabolism. | ACCEPT | Summary: TGF-beta receptor signaling pathway confirmed (PMID:35359452). Reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling. Supporting Evidence: |
| GO:0032924 activin receptor signaling pathway | NAS PMID:15150278 Nodal and ALK7 inhibit proliferation and induce apoptosis in... | ACCEPT | Summary: SMAD3 is an intracellular effector of activin receptors. PMID:9892009 directly examines activin receptor association, release and SMAD4 assembly. PMID:15150278, attached to some seeded rows, principally tests nodal/ALK7 signaling in human trophoblast cells; that paper alone is not ligand-specific evidence for activin. Reason: SMAD3 is an intracellular effector of activin receptors. PMID:9892009 directly examines activin receptor association, release and SMAD4 assembly. PMID:15150278, attached to some seeded rows, principally tests nodal/ALK7 signaling in human trophoblast cells; that paper alone is not ligand-specific evidence for activin. Supporting Evidence: PMID:9892009 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. PMID:12844345 Using p3TP-luc, the H295R cells show transcriptional activation of this activin-responsive reporter in the presence of activin A. |
| GO:0005634 nucleus | IPI PMID:20935647 IL-37 is a fundamental inhibitor of innate immunity. | ACCEPT | Summary: Nucleus localization confirmed (PMID:20935647). SMAD3 translocates to nucleus upon TGF-beta activation. Reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation. Supporting Evidence: |
| GO:0005737 cytoplasm | IPI PMID:20935647 IL-37 is a fundamental inhibitor of innate immunity. | ACCEPT | Summary: Cytoplasm localization confirmed (PMID:20935647). SMAD3 resides in cytoplasm before activation. Reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus. Supporting Evidence: |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:25060702 A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent... | MODIFY | Summary: SMAD3 directly activates and represses RNA polymerase II transcription in distinct promoter contexts. Replace the general regulation term with both supported directional descendants, rather than discarding either activity. Reason: SMAD3 directly activates and represses RNA polymerase II transcription in distinct promoter contexts. Replace the general regulation term with both supported directional descendants, rather than discarding either activity. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0031665 negative regulation of lipopolysaccharide-mediated signaling pathway | NAS PMID:29789615 IL-37 isoform D downregulates pro-inflammatory cytokines exp... | KEEP AS NON CORE | Summary: Negative regulation of LPS-mediated signaling pathway (PMID:29789615). NAS from ComplexPortal. Reason: Valid downstream effect reflecting anti-inflammatory role of TGF-beta/SMAD3. Non-core immune process. Supporting Evidence: |
| GO:0050728 negative regulation of inflammatory response | NAS PMID:27060871 Suppression of innate inflammation and immunity by interleuk... | KEEP AS NON CORE | Summary: Negative regulation of inflammatory response (PMID:27060871). NAS from ComplexPortal. Reason: Valid downstream effect. TGF-beta/SMAD3 is a key anti-inflammatory pathway. Non-core immune process. Supporting Evidence: |
| GO:0071635 negative regulation of transforming growth factor beta production | NAS PMID:20935647 IL-37 is a fundamental inhibitor of innate immunity. | UNDECIDED | Summary: The IL-37 study supports SMAD3-dependent suppression of inflammatory cytokines, but the specific reduction of TGF-beta production could not be verified in the accessible material. This is not a claim that the experimental curation is misattributed. Reason: The IL-37 study supports SMAD3-dependent suppression of inflammatory cytokines, but the specific reduction of TGF-beta production could not be verified in the accessible material. This is not a claim that the experimental curation is misattributed. Supporting Evidence: |
| GO:0061450 trophoblast cell migration | IDA PMID:34432647 GDF-8 stimulates trophoblast cell invasion by inducing ALK5-... | KEEP AS NON CORE | Summary: Trophoblast cell migration (PMID:34432647). Reason: Specific developmental process. TGF-beta/SMAD3 promotes trophoblast migration. Non-core tissue-specific process. Supporting Evidence: |
| GO:0045596 negative regulation of cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of cell differentiation (GO_REF:0000024). ISS from mouse ortholog. Reason: Valid downstream effect. TGF-beta/SMAD3 can inhibit differentiation in certain contexts. Non-core pleiotropic process. Supporting Evidence: |
| GO:0060391 positive regulation of SMAD protein signal transduction | IMP PMID:15107418 Activin receptor-like kinase-7 induces apoptosis through act... | UNDECIDED | Summary: The study supports SMAD3-dependent signaling downstream of activated ALK7 in apoptosis. The accessible material does not resolve the additional assertion that SMAD3 positively regulates the SMAD signaling pathway rather than transducing it; retain the seeded claim as unresolved. Reason: The study supports SMAD3-dependent signaling downstream of activated ALK7 in apoptosis. The accessible material does not resolve the additional assertion that SMAD3 positively regulates the SMAD signaling pathway rather than transducing it; retain the seeded claim as unresolved. Supporting Evidence: |
| GO:0097190 apoptotic signaling pathway | IMP PMID:15107418 Activin receptor-like kinase-7 induces apoptosis through act... | KEEP AS NON CORE | Summary: Apoptotic signaling pathway (PMID:15107418). Reason: Valid downstream effect. TGF-beta/SMAD3 can trigger apoptosis in certain contexts. Non-core pleiotropic process. Supporting Evidence: |
| GO:0030279 negative regulation of ossification | IDA PMID:22155034 Bone morphogenetic protein-3b (BMP-3b) inhibits osteoblast d... | KEEP AS NON CORE | Summary: Negative regulation of ossification (PMID:22155034). Reason: Valid downstream effect. UniProt notes SMAD3 inhibits early healing of bone fractures. Non-core tissue-specific process. Supporting Evidence: |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IMP PMID:8774881 Receptor-associated Mad homologues synergize as effectors of... | ACCEPT | Summary: TGF-beta receptor signaling pathway confirmed (PMID:8774881). Reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling. Supporting Evidence: |
| GO:0060395 SMAD protein signal transduction | IMP PMID:30729664 Novel role of the clustered miR-23b-3p and miR-27b-3p in enh... | ACCEPT | Summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:30729664). Reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction. Supporting Evidence: |
| GO:1901203 positive regulation of extracellular matrix assembly | IMP PMID:30729664 Novel role of the clustered miR-23b-3p and miR-27b-3p in enh... | KEEP AS NON CORE | Summary: Positive regulation of extracellular matrix assembly (PMID:30729664). Reason: Valid downstream effect. TGF-beta/SMAD3 transcriptionally activates ECM genes (collagen, fibronectin). Non-core but well-documented in fibrosis context. Supporting Evidence: |
| GO:1902895 positive regulation of miRNA transcription | IMP PMID:30729664 Novel role of the clustered miR-23b-3p and miR-27b-3p in enh... | KEEP AS NON CORE | Summary: Positive regulation of miRNA transcription (PMID:30729664). Reason: Valid specific function. SMAD3 regulates miRNA transcription at specific loci. Non-core regulatory process. Supporting Evidence: |
| GO:1990776 response to angiotensin | IMP PMID:30729664 Novel role of the clustered miR-23b-3p and miR-27b-3p in enh... | KEEP AS NON CORE | Summary: Response to angiotensin (PMID:30729664). Acts upstream of. Reason: TGF-beta/SMAD3 signaling cross-talks with angiotensin pathways in cardiovascular/fibrotic contexts. Non-core. Supporting Evidence: |
| GO:0060395 SMAD protein signal transduction | IDA PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | ACCEPT | Summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:9732876). Reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction. Supporting Evidence: PMID:9732876 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. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:15781469 CHIP controls the sensitivity of transforming growth factor-... | KEEP AS NON CORE | Summary: Binding to E3 ubiquitin ligases regulates SMAD3 ubiquitination, turnover and signaling duration. CHIP and Smurf2 studies support this interaction independently of the broader Smurf1/Smad7 focus of PMID:11278251. This is a regulatory interaction rather than SMAD3 catalytic ubiquitin-ligase activity. Reason: Binding to E3 ubiquitin ligases regulates SMAD3 ubiquitination, turnover and signaling duration. CHIP and Smurf2 studies support this interaction independently of the broader Smurf1/Smad7 focus of PMID:11278251. This is a regulatory interaction rather than SMAD3 catalytic ubiquitin-ligase activity. Supporting Evidence: PMID:15781469 Finally, we demonstrated that CHIP served as a U-box dependent E3 ligase that can directly mediate ubiquitination and degradation of Smad3 and that this action of CHIP was independent of TGF-beta signaling. PMID:19122240 Pin1 interacted with Smad2 and Smad3 but not Smad4; this interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region. (S/T)P motif phosphorylation also enhanced the interaction of Smad2/3 with Smurf2. |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IDA PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: TGF-beta receptor signaling pathway confirmed (PMID:9311995). Reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0060395 SMAD protein signal transduction | IDA PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:9311995). Reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0001222 transcription corepressor binding | IPI PMID:14612439 A novel E1A-like inhibitor of differentiation (EID) family m... | ACCEPT | Summary: Transcription corepressor binding confirmed. SMAD3 interacts with corepressors including Ski, SnoN, TGIF (PMID:14612439). Reason: Well-supported. SMAD3 recruits transcriptional corepressors at certain target genes. Supporting Evidence: |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:10823886 Transforming growth factor beta -inducible independent bindi... | MODIFY | Summary: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Reason: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IDA PMID:10823886 Transforming growth factor beta -inducible independent bindi... | ACCEPT | Summary: TGF-beta receptor signaling pathway confirmed (PMID:10823886). Reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling. Supporting Evidence: |
| GO:0060395 SMAD protein signal transduction | IDA PMID:10823886 Transforming growth factor beta -inducible independent bindi... | ACCEPT | Summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:10823886). Reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction. Supporting Evidence: |
| GO:0060395 SMAD protein signal transduction | IDA PMID:9111321 Heteromeric and homomeric interactions correlate with signal... | ACCEPT | Summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:9111321). Reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction. Supporting Evidence: PMID:9111321 We now show that Smad3 and Smad4 associate in homomeric and heteromeric interactions, as assessed by yeast two-hybrid and coimmunoprecipitation analyses. |
| GO:0000987 cis-regulatory region sequence-specific DNA binding | IMP PMID:32141990 miR-4286/TGF-Ξ²1/Smad3-Negative Feedback Loop Ameliorated Vas... | ACCEPT | Summary: Cis-regulatory region sequence-specific DNA binding confirmed (PMID:32141990). Reason: Core molecular function. SMAD3 binds SBE sequences in cis-regulatory regions. Supporting Evidence: PMID:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0003700 DNA-binding transcription factor activity | IMP PMID:32141990 miR-4286/TGF-Ξ²1/Smad3-Negative Feedback Loop Ameliorated Vas... | MODIFY | Summary: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Reason: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:1902894 negative regulation of miRNA transcription | IMP PMID:32141990 miR-4286/TGF-Ξ²1/Smad3-Negative Feedback Loop Ameliorated Vas... | KEEP AS NON CORE | Summary: Negative regulation of miRNA transcription (PMID:32141990). Reason: Valid specific function. SMAD3 can also repress miRNA transcription at certain loci. Non-core regulatory process. Supporting Evidence: PMID:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:24378993 Crosstalk between TGF-Ξ²/Smad3 and BMP/BMPR2 signaling pathwa... | ACCEPT | Summary: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Reason: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. PMID:9732876 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. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:24378993 Crosstalk between TGF-Ξ²/Smad3 and BMP/BMPR2 signaling pathwa... | ACCEPT | Summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:24378993). Reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes. Supporting Evidence: |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IMP PMID:24378993 Crosstalk between TGF-Ξ²/Smad3 and BMP/BMPR2 signaling pathwa... | ACCEPT | Summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:24378993). Reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes. Supporting Evidence: |
| GO:0010629 negative regulation of gene expression | IMP PMID:24378993 Crosstalk between TGF-Ξ²/Smad3 and BMP/BMPR2 signaling pathwa... | KEEP AS NON CORE | Summary: SMAD-dependent induction of the miR-17-92 cluster decreases BMPR2 expression post-transcriptionally. This is a supported negative regulation of gene expression in that context, not direct transcriptional repression by SMAD3 at the BMPR2 promoter. Reason: SMAD-dependent induction of the miR-17-92 cluster decreases BMPR2 expression post-transcriptionally. This is a supported negative regulation of gene expression in that context, not direct transcriptional repression by SMAD3 at the BMPR2 promoter. Supporting Evidence: |
| GO:1902895 positive regulation of miRNA transcription | IDA PMID:24378993 Crosstalk between TGF-Ξ²/Smad3 and BMP/BMPR2 signaling pathwa... | KEEP AS NON CORE | Summary: Positive regulation of miRNA transcription (PMID:24378993). Reason: Valid specific function. SMAD3 regulates miRNA transcription at specific loci. Non-core regulatory process. Supporting Evidence: |
| GO:1902895 positive regulation of miRNA transcription | IMP PMID:24378993 Crosstalk between TGF-Ξ²/Smad3 and BMP/BMPR2 signaling pathwa... | KEEP AS NON CORE | Summary: Positive regulation of miRNA transcription (PMID:24378993). Reason: Valid specific function. SMAD3 regulates miRNA transcription at specific loci. Non-core regulatory process. Supporting Evidence: |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2179276 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005515 protein binding | IPI PMID:15051726 Atrophin-1-interacting protein 4/human Itch is a ubiquitin E... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:29899023 NEDD9 targets COL3A1 to promote endothelial fibrosis and pul... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISS PMID:24964035 Pin1 promotes degradation of Smad proteins and their interac... | ACCEPT | Summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:24964035). Reason: Activator activity is independently established by SMAD3 reporter and promoter experiments. The attached Pin1/Alzheimer study examines SMAD regulation but is not required as the sole support for this general activity. Supporting Evidence: PMID:9732876 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. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:25605017 Reduction of miR-29c enhances pancreatic cancer cell migrati... | ACCEPT | Summary: SMAD3 transcriptional activator activity is independently established by direct reporter/promoter studies. The attached PMID:25605017 instead demonstrates repression of MIR29C and should not be used by itself as evidence for activation at that locus. Retain the true activity while recording that citation-scope mismatch. Reason: SMAD3 transcriptional activator activity is independently established by direct reporter/promoter studies. The attached PMID:25605017 instead demonstrates repression of MIR29C and should not be used by itself as evidence for activation at that locus. Retain the true activity while recording that citation-scope mismatch. Supporting Evidence: PMID:9732876 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. |
| GO:0032810 sterol response element binding | IGI PMID:25605017 Reduction of miR-29c enhances pancreatic cancer cell migrati... | KEEP AS NON CORE | Summary: The full text explicitly calls the tested MIR29C promoter element a sterol regulatory element (SRE) and reports SMAD3 occupancy. Retain this locus-specific binding annotation; do not silently reinterpret the authors' element name or generalize it to sterol homeostasis. Reason: The full text explicitly calls the tested MIR29C promoter element a sterol regulatory element (SRE) and reports SMAD3 occupancy. Retain this locus-specific binding annotation; do not silently reinterpret the authors' element name or generalize it to sterol homeostasis. Supporting Evidence: |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | ACCEPT | Summary: SMAD3 binds Pol II-specific DNA-binding TFs including c-Jun, c-Fos, PAX6 (PMID:9732876). Reason: Core molecular function. SMAD3 cooperates with other TFs at composite promoter elements. Supporting Evidence: PMID:9732876 Smad3 and Smad4 also act together with c-Jun and c-Fos to activate transcription in response to TGF-beta, through a TGF-beta-inducible association of c-Jun with Smad3 and an interaction of Smad3 and c-Fos |
| GO:0140297 DNA-binding transcription factor binding | IPI PMID:21828274 HEB and E2A function as SMAD/FOXH1 cofactors. | MODIFY | Summary: SMAD3 binds HEB/E2A transcription factors involved in RNA polymerase II target regulation. The existing polymerase-specific transcription-factor-binding term refines the general binding annotation. Reason: SMAD3 binds HEB/E2A transcription factors involved in RNA polymerase II target regulation. The existing polymerase-specific transcription-factor-binding term refines the general binding annotation. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: |
| GO:0016922 nuclear receptor binding | IPI PMID:31023188 LRP1 Deficiency in Vascular SMC Leads to Pulmonary Arterial ... | KEEP AS NON CORE | Summary: The PPARgamma study supports context-dependent nuclear receptor association with SMAD3. This regulatory cross-talk is retained as non-core rather than treated as SMAD3 nuclear-receptor activity. Reason: The PPARgamma study supports context-dependent nuclear receptor association with SMAD3. This regulatory cross-talk is retained as non-core rather than treated as SMAD3 nuclear-receptor activity. Supporting Evidence: |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:14555988 Differential regulation of TGF-beta signaling through Smad2,... | KEEP AS NON CORE | Summary: Negative regulation of cell population proliferation confirmed (PMID:14555988). Reason: Valid downstream effect. TGF-beta/SMAD3 mediates growth arrest through CDK inhibitor induction. Non-core but important pleiotropic process. Supporting Evidence: |
| GO:1902893 regulation of miRNA transcription | IC PMID:25605017 Reduction of miR-29c enhances pancreatic cancer cell migrati... | MODIFY | Summary: The full paper shows SMAD3-dependent repression of MIR29C. Refine general miRNA transcription regulation to the already present negative regulation term; Wnt activation downstream of miR29c repression does not reverse the sign of the primary transcriptional effect. Reason: The full paper shows SMAD3-dependent repression of MIR29C. Refine general miRNA transcription regulation to the already present negative regulation term; Wnt activation downstream of miR29c repression does not reverse the sign of the primary transcriptional effect. Proposed replacements: negative regulation of miRNA transcription Supporting Evidence: |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:28467929 PPARΞ³ Links BMP2 and TGFΞ²1 Pathways in Vascular Smooth Muscl... | ACCEPT | Summary: Negative regulation of transcription by Pol II confirmed (PMID:28467929). SMAD3 can repress transcription. Reason: Valid. SMAD3 acts as transcriptional repressor at certain loci with Ski/SnoN/TGIF cofactors. Supporting Evidence: |
| GO:0001217 DNA-binding transcription repressor activity | IDA PMID:28467929 PPARΞ³ Links BMP2 and TGFΞ²1 Pathways in Vascular Smooth Muscl... | ACCEPT | Summary: DNA-binding transcription repressor activity confirmed (PMID:28467929). SMAD3 can also repress transcription at certain loci. Reason: Valid. SMAD3 acts as both activator and repressor depending on cofactor context (Ski/SnoN, TGIF for repression). Supporting Evidence: |
| GO:0003677 DNA binding | IDA PMID:28467929 PPARΞ³ Links BMP2 and TGFΞ²1 Pathways in Vascular Smooth Muscl... | MODIFY | Summary: DNA binding is established, but the existing RNA polymerase II cis-regulatory region sequence-specific DNA-binding annotation describes the demonstrated specificity more precisely. Reason: DNA binding is established, but the existing RNA polymerase II cis-regulatory region sequence-specific DNA-binding annotation describes the demonstrated specificity more precisely. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. PMID:9732876 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. |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IDA PMID:28467929 PPARΞ³ Links BMP2 and TGFΞ²1 Pathways in Vascular Smooth Muscl... | ACCEPT | Summary: TGF-beta receptor signaling pathway confirmed (PMID:28467929). Reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling. Supporting Evidence: |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9731111 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IMP PMID:26311719 MicroRNA-143 Activation Regulates Smooth Muscle and Endothel... | ACCEPT | Summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:26311719). Reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes. Supporting Evidence: |
| GO:1902895 positive regulation of miRNA transcription | IMP PMID:26311719 MicroRNA-143 Activation Regulates Smooth Muscle and Endothel... | KEEP AS NON CORE | Summary: Positive regulation of miRNA transcription (PMID:26311719). Reason: Valid specific function. SMAD3 regulates miRNA transcription at specific loci. Non-core regulatory process. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:23723426 Kindlin-2 mediates activation of TGF-Ξ²/Smad signaling and re... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005634 nucleus | IGI PMID:23723426 Kindlin-2 mediates activation of TGF-Ξ²/Smad signaling and re... | ACCEPT | Summary: Nucleus localization confirmed (PMID:23723426). SMAD3 translocates to nucleus upon TGF-beta activation. Reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation. Supporting Evidence: |
| GO:0005829 cytosol | IGI PMID:23723426 Kindlin-2 mediates activation of TGF-Ξ²/Smad signaling and re... | ACCEPT | Summary: Cytosol localization (PMID:23723426). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. Supporting Evidence: |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:18832382 HMGA2 and Smads co-regulate SNAIL1 expression during inducti... | ACCEPT | Summary: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Reason: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. PMID:9732876 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. |
| GO:0005634 nucleus | IDA PMID:21145499 The Crumbs complex couples cell density sensing to Hippo-dep... | ACCEPT | Summary: Nucleus localization confirmed (PMID:21145499). SMAD3 translocates to nucleus upon TGF-beta activation. Reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:21145499 The Crumbs complex couples cell density sensing to Hippo-dep... | ACCEPT | Summary: Cytoplasm localization confirmed (PMID:21145499). SMAD3 resides in cytoplasm before activation. Reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus. Supporting Evidence: |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:31582430 Structural basis for distinct roles of SMAD2 and SMAD3 in FO... | ACCEPT | Summary: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Reason: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. PMID:9732876 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. |
| GO:0001223 transcription coactivator binding | IPI PMID:16777850 The novel PIAS-like protein hZimp10 enhances Smad transcript... | ACCEPT | Summary: Transcription coactivator binding confirmed. SMAD3 interacts with coactivators including p300/CBP, ZMIZ1 (PMID:16777850). Reason: Well-supported. SMAD3 linker region and MH2 domain recruit p300/CBP coactivators. Supporting Evidence: |
| GO:0000987 cis-regulatory region sequence-specific DNA binding | IC PMID:21828274 HEB and E2A function as SMAD/FOXH1 cofactors. | ACCEPT | Summary: Cis-regulatory region sequence-specific DNA binding confirmed (PMID:21828274). Reason: Core molecular function. SMAD3 binds SBE sequences in cis-regulatory regions. Supporting Evidence: |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Chromatin localization (GO_REF:0000113). SMAD3 is found at chromatin at TGF-beta target gene loci. Reason: Correct. ChIP studies confirm SMAD3 binding to chromatin at enhancer/promoter regions. Supporting Evidence: |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: SMAD3 is a direct DNA-binding regulator of RNA polymerase II transcription, with activation or repression depending on the promoter and associated factors. This is a core activity shared across its TGF-beta/activin responses. Reason: SMAD3 is a direct DNA-binding regulator of RNA polymerase II transcription, with activation or repression depending on the promoter and associated factors. This is a core activity shared across its TGF-beta/activin responses. Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: SMAD3 is a direct DNA-binding regulator of RNA polymerase II transcription, with activation or repression depending on the promoter and associated factors. This is a core activity shared across its TGF-beta/activin responses. Reason: SMAD3 is a direct DNA-binding regulator of RNA polymerase II transcription, with activation or repression depending on the promoter and associated factors. This is a core activity shared across its TGF-beta/activin responses. Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0042307 positive regulation of protein import into nucleus | NAS PMID:15799969 Nuclear targeting of transforming growth factor-beta-activat... | ACCEPT | Summary: Positive regulation of protein import into nucleus (PMID:15799969). Reason: SMAD3 promotes nuclear import of the SMAD2/3-SMAD4 complex. Part of core signaling mechanism. Supporting Evidence: PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005515 protein binding | IPI PMID:25556234 New host factors important for respiratory syncytial virus (... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IDA PMID:18548003 SMAD proteins control DROSHA-mediated microRNA maturation. | ACCEPT | Summary: TGF-beta receptor signaling pathway confirmed (PMID:18548003). Reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling. Supporting Evidence: PMID:18548003 TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. |
| GO:0017151 DEAD/H-box RNA helicase binding | IPI PMID:18548003 SMAD proteins control DROSHA-mediated microRNA maturation. | KEEP AS NON CORE | Summary: R-SMAD interaction with the DDX5/p68-DROSHA microprocessor supports pri-miRNA maturation after TGF-beta stimulation. Retain the RNA-helicase interaction as a secondary post-transcriptional function; it is separable from SMAD3 DNA-binding transcriptional activity. Reason: R-SMAD interaction with the DDX5/p68-DROSHA microprocessor supports pri-miRNA maturation after TGF-beta stimulation. Retain the RNA-helicase interaction as a secondary post-transcriptional function; it is separable from SMAD3 DNA-binding transcriptional activity. Supporting Evidence: PMID:18548003 TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. |
| GO:0005515 protein binding | IPI PMID:24613385 Hsp70 and Hsp90 oppositely regulate TGF-Ξ² signaling through ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0031962 nuclear mineralocorticoid receptor binding | IPI PMID:12902338 Identification of glucocorticoid receptor domains involved i... | UNDECIDED | Summary: The accessible abstract directly verifies glucocorticoid-receptor binding to SMAD3 and reports that the mineralocorticoid receptor did not reproduce transcriptional repression. That is neither positive nor negative proof of mineralocorticoid-receptor binding. The full binding experiment remains unavailable, so do not overrule this experimental annotation. Reason: The accessible abstract directly verifies glucocorticoid-receptor binding to SMAD3 and reports that the mineralocorticoid receptor did not reproduce transcriptional repression. That is neither positive nor negative proof of mineralocorticoid-receptor binding. The full binding experiment remains unavailable, so do not overrule this experimental annotation. Supporting Evidence: |
| GO:0035259 nuclear glucocorticoid receptor binding | IPI PMID:12902338 Identification of glucocorticoid receptor domains involved i... | KEEP AS NON CORE | Summary: Nuclear glucocorticoid receptor binding. SMAD3 interacts with NR3C1 (PMID:12902338). Reason: Documented interaction representing transcriptional cross-talk between TGF-beta and glucocorticoid signaling. Supporting Evidence: |
| GO:0071560 cellular response to transforming growth factor beta stimulus | IDA PMID:12902338 Identification of glucocorticoid receptor domains involved i... | ACCEPT | Summary: Cellular response to TGF-beta stimulus confirmed (PMID:12902338). Reason: Core biological process. SMAD3 is a primary mediator of cellular TGF-beta responses. Supporting Evidence: |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | IDA PMID:27038547 MiRNA-199a-5p influences pulmonary artery hypertension via d... | KEEP AS NON CORE | Summary: Positive regulation of nitric oxide biosynthetic process (PMID:27038547). Reason: Specific downstream effect in certain cell types. Non-core pleiotropic process. Supporting Evidence: PMID:27038547 Mechanism analyses revealed that the downregulation of NO and the upregulation of Ca(2+) caused by miR-199a-5p were all reversed by Smad3 overexpression in HPASMCs and HPAECs. |
| GO:0051481 negative regulation of cytosolic calcium ion concentration | IDA PMID:27038547 MiRNA-199a-5p influences pulmonary artery hypertension via d... | KEEP AS NON CORE | Summary: Human pulmonary vascular-cell experiments link miR-199a-5p suppression of SMAD3 to reduced nitric oxide and elevated intracellular calcium, with SMAD3 restoration reversing these changes. Transcriptional regulation can mediate a calcium response; the annotation does not claim that SMAD3 is a calcium transporter or calcium-binding protein. Reason: Human pulmonary vascular-cell experiments link miR-199a-5p suppression of SMAD3 to reduced nitric oxide and elevated intracellular calcium, with SMAD3 restoration reversing these changes. Transcriptional regulation can mediate a calcium response; the annotation does not claim that SMAD3 is a calcium transporter or calcium-binding protein. Supporting Evidence: PMID:27038547 Mechanism analyses revealed that the downregulation of NO and the upregulation of Ca(2+) caused by miR-199a-5p were all reversed by Smad3 overexpression in HPASMCs and HPAECs. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6781764 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005634 nucleus | IDA PMID:25893292 Syntenin regulates TGF-Ξ²1-induced Smad activation and the ep... | ACCEPT | Summary: Nucleus localization confirmed (PMID:25893292). SMAD3 translocates to nucleus upon TGF-beta activation. Reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation. Supporting Evidence: |
| GO:0045599 negative regulation of fat cell differentiation | IDA PMID:19816956 MiR-21 regulates adipogenic differentiation through the modu... | KEEP AS NON CORE | Summary: Negative regulation of fat cell differentiation (PMID:19816956). Reason: Valid downstream effect. TGF-beta/SMAD3 inhibits adipogenesis. Non-core tissue-specific process. Supporting Evidence: |
| GO:1901203 positive regulation of extracellular matrix assembly | IDA PMID:21307346 Response gene to complement 32 interacts with Smad3 to promo... | KEEP AS NON CORE | Summary: Positive regulation of extracellular matrix assembly (PMID:21307346). Reason: Valid downstream effect. TGF-beta/SMAD3 transcriptionally activates ECM genes (collagen, fibronectin). Non-core but well-documented in fibrosis context. Supporting Evidence: |
| GO:0005634 nucleus | IDA PMID:16007207 Hepatitis C virus core variants isolated from liver tumor bu... | ACCEPT | Summary: Nucleus localization confirmed (PMID:16007207). SMAD3 translocates to nucleus upon TGF-beta activation. Reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation. Supporting Evidence: |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Reason: SMAD3 directly binds sequence-specific regulatory DNA and occupies RNA polymerase II target promoters. MH1-DNA structures and promoter assays establish this function independently of the annotation source; the inference does not extend indiscriminately to every SMAD family member. Supporting Evidence: PMID:12686552 The crystal structure of a Smad3 MH1 domain bound to a palindromic DNA sequence, determined at 2.4-A resolution, reveals a surprisingly important role for water molecules. PMID:9732876 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. |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | MODIFY | Summary: Both activation and repression of RNA polymerase II transcription are supported; use the two existing directional terms. Reason: Both activation and repression of RNA polymerase II transcription are supported; use the two existing directional terms. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:14555988 Differential regulation of TGF-beta signaling through Smad2,... | ACCEPT | Summary: Positive regulation of Pol II transcription confirmed (PMID:14555988). Reason: Core biological process. SMAD3 activates transcription of TGF-beta responsive genes. Supporting Evidence: |
| GO:0010628 positive regulation of gene expression | IDA PMID:21307346 Response gene to complement 32 interacts with Smad3 to promo... | MODIFY | Summary: The study supports SMAD3-dependent fibronectin gene induction during matrix production. Refine positive gene-expression regulation to the supported RNA polymerase II transcriptional output already represented here. Reason: The study supports SMAD3-dependent fibronectin gene induction during matrix production. Refine positive gene-expression regulation to the supported RNA polymerase II transcriptional output already represented here. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:20129061 TMEPAI, a transmembrane TGF-beta-inducible protein, sequeste... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:24627487 C18 ORF1, a novel negative regulator of transforming growth ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0070412 R-SMAD binding | IPI PMID:20129061 TMEPAI, a transmembrane TGF-beta-inducible protein, sequeste... | ACCEPT | Summary: SMAD3 forms complexes with receptor-regulated SMAD proteins, including SMAD2, as shown by the TGF-beta-induced interaction study. PMID:20129061 studies TMEPAI binding to R-SMADs; the independent SMAD-complex study is used here to support SMAD3 itself as the binder. Reason: SMAD3 forms complexes with receptor-regulated SMAD proteins, including SMAD2, as shown by the TGF-beta-induced interaction study. PMID:20129061 studies TMEPAI binding to R-SMADs; the independent SMAD-complex study is used here to support SMAD3 itself as the binder. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0000785 chromatin | IDA PMID:21828274 HEB and E2A function as SMAD/FOXH1 cofactors. | ACCEPT | Summary: Chromatin localization (PMID:21828274). SMAD3 is found at chromatin at TGF-beta target gene loci. Reason: Correct. ChIP studies confirm SMAD3 binding to chromatin at enhancer/promoter regions. Supporting Evidence: |
| GO:0043425 bHLH transcription factor binding | IPI PMID:21828274 HEB and E2A function as SMAD/FOXH1 cofactors. | ACCEPT | Summary: bHLH transcription factor binding. SMAD3 binds HEB/TCF12 (PMID:21828274). Reason: Documented interaction between SMAD3 and bHLH TFs at target gene promoters. Supporting Evidence: |
| GO:0071144 heteromeric SMAD protein complex | IDA PMID:21828274 HEB and E2A function as SMAD/FOXH1 cofactors. | ACCEPT | Summary: Phosphorylated SMAD3 assembles with SMAD4 into a heteromeric signaling complex. Structural analysis establishes two phosphorylated R-SMAD subunits with one SMAD4; this does not imply that every SMAD3 response requires SMAD4. Reason: Phosphorylated SMAD3 assembles with SMAD4 into a heteromeric signaling complex. Structural analysis establishes two phosphorylated R-SMAD subunits with one SMAD4; this does not imply that every SMAD3 response requires SMAD4. Supporting Evidence: PMID:15350224 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:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0097191 extrinsic apoptotic signaling pathway | IMP PMID:15334054 Hepatitis C viral proteins interact with Smad3 and different... | KEEP AS NON CORE | Summary: Extrinsic apoptotic signaling pathway (PMID:15334054). Reason: Valid downstream effect. Non-core pleiotropic process. Supporting Evidence: |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2176475 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2176491 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2176502 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2176503 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2179274 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-1535903 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-173481 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-173488 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-173545 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-209055 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2106579 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2127257 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2186607 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2186643 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187309 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187325 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187330 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187388 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-870449 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-870538 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878143 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878178 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952226 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9617996 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9618004 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9618021 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9733207 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9733247 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736959 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736970 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736979 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736984 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736992 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9737710 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9823952 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9823959 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-2186736 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-2186755 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9625758 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3315483 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187395 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1549526 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170847 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170850 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170868 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-173488 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2031355 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2106579 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187355 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187401 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187405 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3311014 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9008928 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9009910 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0000987 cis-regulatory region sequence-specific DNA binding | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: Cis-regulatory region sequence-specific DNA binding confirmed (PMID:21947082). Reason: Core molecular function. SMAD3 binds SBE sequences in cis-regulatory regions. Supporting Evidence: |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | MODIFY | Summary: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Reason: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0005515 protein binding | IPI PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005634 nucleus | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: Nucleus localization confirmed (PMID:21947082). SMAD3 translocates to nucleus upon TGF-beta activation. Reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation. Supporting Evidence: |
| GO:0005667 transcription regulator complex | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: Transcription regulator complex confirmed (PMID:21947082). SMAD3 forms complexes with SMAD4 and cofactors. Reason: Correct. SMAD3/SMAD4 heteromeric complexes function as transcription regulator complexes. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: Cytoplasm localization confirmed (PMID:21947082). SMAD3 resides in cytoplasm before activation. Reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus. Supporting Evidence: |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: TGF-beta receptor signaling pathway confirmed (PMID:21947082). Reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling. Supporting Evidence: |
| GO:0071141 SMAD protein complex | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: SMAD protein complex confirmed (PMID:21947082). Reason: Correct. SMAD3 forms SMAD protein complexes including homo-oligomers and hetero-complexes with SMAD4. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21307346 Response gene to complement 32 interacts with Smad3 to promo... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0010718 positive regulation of epithelial to mesenchymal transition | IDA PMID:21307346 Response gene to complement 32 interacts with Smad3 to promo... | KEEP AS NON CORE | Summary: Positive regulation of EMT (PMID:21307346). Reason: Valid downstream effect. TGF-beta/SMAD3 is a major driver of EMT. Non-core but well-documented process. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19289081 Nuclear export of Smad2 and Smad3 by RanBP3 facilitates term... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:9865696 SARA, a FYVE domain protein that recruits Smad2 to the TGFbe... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:9892009 Roles of pathway-specific and inhibitory Smads in activin re... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0032924 activin receptor signaling pathway | IMP PMID:15150278 Nodal and ALK7 inhibit proliferation and induce apoptosis in... | ACCEPT | Summary: SMAD3 is an intracellular effector of activin receptors. PMID:9892009 directly examines activin receptor association, release and SMAD4 assembly. PMID:15150278, attached to some seeded rows, principally tests nodal/ALK7 signaling in human trophoblast cells; that paper alone is not ligand-specific evidence for activin. Reason: SMAD3 is an intracellular effector of activin receptors. PMID:9892009 directly examines activin receptor association, release and SMAD4 assembly. PMID:15150278, attached to some seeded rows, principally tests nodal/ALK7 signaling in human trophoblast cells; that paper alone is not ligand-specific evidence for activin. Supporting Evidence: PMID:9892009 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. PMID:12844345 Using p3TP-luc, the H295R cells show transcriptional activation of this activin-responsive reporter in the presence of activin A. |
| GO:0038092 nodal signaling pathway | IMP PMID:15150278 Nodal and ALK7 inhibit proliferation and induce apoptosis in... | ACCEPT | Summary: Nodal signaling pathway (PMID:15150278). Reason: SMAD3 also mediates Nodal signaling, which uses the same R-SMAD pathway as activin/TGF-beta. Supporting Evidence: PMID:15150278 The growth inhibitory effect of Nodal was also blocked by dominant-negative Smad2/3. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170835 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187358 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187368 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187375 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187382 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187395 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3656523 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9008692 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9727922 | ACCEPT | Summary: SMAD3 occupies nuclear and cytosolic pools during receptor-regulated signaling. Reason: Retain this subcellular location, independently supported by experimental SMAD3 trafficking studies. A Reactome reaction involving a mutant or a regulator is not evidence that wild-type SMAD3 has that mutant activity, but does not invalidate its location. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15799969 Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. |
| GO:0005515 protein binding | IPI PMID:10681527 Identification and characterization of a PDZ protein that in... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0043130 ubiquitin binding | IDA PMID:18794808 Ligand-dependent ubiquitination of Smad3 is regulated by cas... | UNDECIDED | Summary: The study establishes CK1gamma2-dependent SMAD3 phosphorylation and ubiquitination/degradation. Covalent ubiquitination does not establish noncovalent ubiquitin binding. The accessible evidence does not verify the specific binding assay underlying this annotation; retain uncertainty rather than infer a ubiquitin-binding activity from substrate modification. Reason: The study establishes CK1gamma2-dependent SMAD3 phosphorylation and ubiquitination/degradation. Covalent ubiquitination does not establish noncovalent ubiquitin binding. The accessible evidence does not verify the specific binding assay underlying this annotation; retain uncertainty rather than infer a ubiquitin-binding activity from substrate modification. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17469184 Involvement of the constitutive complex formation of c-Ski/S... | MODIFY | Summary: The cited study supports c-Ski/SnoN corepressor association with SMAD complexes. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports c-Ski/SnoN corepressor association with SMAD complexes. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:18832382 HMGA2 and Smads co-regulate SNAIL1 expression during inducti... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:18832382 HMGA2 and Smads co-regulate SNAIL1 expression during inducti... | ACCEPT | Summary: Positive regulation of Pol II transcription confirmed (PMID:18832382). Reason: Core biological process. SMAD3 activates transcription of TGF-beta responsive genes. Supporting Evidence: |
| GO:0071141 SMAD protein complex | IDA PMID:18832382 HMGA2 and Smads co-regulate SNAIL1 expression during inducti... | ACCEPT | Summary: SMAD protein complex confirmed (PMID:18832382). Reason: Correct. SMAD3 forms SMAD protein complexes including homo-oligomers and hetero-complexes with SMAD4. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:15588252 The Smad3 linker region contains a transcriptional activatio... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0008270 zinc ion binding | IDA PMID:12686552 Features of a Smad3 MH1-DNA complex. Roles of water and zinc... | ACCEPT | Summary: Zinc ion binding confirmed (PMID:12686552). SMAD3 MH1 domain coordinates zinc via Cys and His residues. Reason: Crystal structure confirms zinc coordination in MH1 domain essential for DNA binding (PMID:12686552). Supporting Evidence: PMID:12686552 In addition, the MH1 domain is found to contain a bound zinc atom using four invariant residues among Smad proteins, three cysteines and one histidine. |
| GO:0019902 phosphatase binding | IPI PMID:16751101 PPM1A functions as a Smad phosphatase to terminate TGFbeta s... | MODIFY | Summary: Refine the general phosphatase-binding term to protein phosphatase binding. PPM1A is the original reported partner, but PMID:16751101 has editorial notices; independent MTMR4 binding/dephosphorylation evidence supports the general interaction class. SMAD3 is the bound substrate, not the catalytic phosphatase. Reason: Refine the general phosphatase-binding term to protein phosphatase binding. PPM1A is the original reported partner, but PMID:16751101 has editorial notices; independent MTMR4 binding/dephosphorylation evidence supports the general interaction class. SMAD3 is the bound substrate, not the catalytic phosphatase. Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:16751101 This work demonstrates that PPM1A/PP2Calpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFbeta signaling. PMID:20061380 Co-immunoprecipitation experiments showed that endogenous MTMR4 interacts with phosphorylated R-Smads, and that this interaction is correlated with dephosphorylation of R-Smads. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:17251190 The MH1 domain of Smad3 interacts with Pax6 and represses au... | ACCEPT | Summary: SMAD3 binds Pol II-specific DNA-binding TFs including c-Jun, c-Fos, PAX6 (PMID:17251190). Reason: Core molecular function. SMAD3 cooperates with other TFs at composite promoter elements. Supporting Evidence: PMID:9732876 Smad3 and Smad4 also act together with c-Jun and c-Fos to activate transcription in response to TGF-beta, through a TGF-beta-inducible association of c-Jun with Smad3 and an interaction of Smad3 and c-Fos |
| GO:0005515 protein binding | IPI PMID:18568018 TAZ controls Smad nucleocytoplasmic shuttling and regulates ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:11278251 Smurf1 interacts with transforming growth factor-beta type I... | KEEP AS NON CORE | Summary: Binding to E3 ubiquitin ligases regulates SMAD3 ubiquitination, turnover and signaling duration. CHIP and Smurf2 studies support this interaction independently of the broader Smurf1/Smad7 focus of PMID:11278251. This is a regulatory interaction rather than SMAD3 catalytic ubiquitin-ligase activity. Reason: Binding to E3 ubiquitin ligases regulates SMAD3 ubiquitination, turnover and signaling duration. CHIP and Smurf2 studies support this interaction independently of the broader Smurf1/Smad7 focus of PMID:11278251. This is a regulatory interaction rather than SMAD3 catalytic ubiquitin-ligase activity. Supporting Evidence: PMID:15781469 Finally, we demonstrated that CHIP served as a U-box dependent E3 ligase that can directly mediate ubiquitination and degradation of Smad3 and that this action of CHIP was independent of TGF-beta signaling. PMID:19122240 Pin1 interacted with Smad2 and Smad3 but not Smad4; this interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region. (S/T)P motif phosphorylation also enhanced the interaction of Smad2/3 with Smurf2. |
| GO:0005515 protein binding | IPI PMID:15897867 Oligomerization of Evi-1 regulated by the PR domain contribu... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:17099224 Potentiation of Smad-mediated transcriptional activation by ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:15647271 The integral inner nuclear membrane protein MAN1 physically ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005637 nuclear inner membrane | IDA PMID:15647271 The integral inner nuclear membrane protein MAN1 physically ... | KEEP AS NON CORE | Summary: Nuclear inner membrane localization (PMID:15647271). SMAD3 co-localizes with LEMD3/MAN1. Reason: SMAD3 interacts with LEMD3/MAN1 at the nuclear inner membrane, which sequesters SMAD3 to antagonize signaling. Specialized localization. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19049980 SKI and MEL1 cooperate to inhibit transforming growth factor... | MODIFY | Summary: The cited study supports SKI-associated transcriptional repression by the SMAD3-SKI complex. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Reason: The cited study supports SKI-associated transcriptional repression by the SMAD3-SKI complex. Replace bare protein binding with the informative interaction class rather than discarding the demonstrated interaction. Proposed replacements: transcription corepressor binding Supporting Evidence: |
| GO:0019901 protein kinase binding | IPI PMID:12874272 Requirement of the co-repressor homeodomain-interacting prot... | MODIFY | Summary: SMAD3 binding to serine/threonine kinases is directly supported by receptor and CK1gamma2 studies. Refine kinase binding accordingly. The seeded PMID:12874272 concerns HIPK2/SKI signaling, not the previously claimed CDK8/CDK9 experiments; no specific CDK interaction is inferred from that citation. Reason: SMAD3 binding to serine/threonine kinases is directly supported by receptor and CK1gamma2 studies. Refine kinase binding accordingly. The seeded PMID:12874272 concerns HIPK2/SKI signaling, not the previously claimed CDK8/CDK9 experiments; no specific CDK interaction is inferred from that citation. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:17327236 In this study we show that PDK1 coimmunoprecipitates with Smad proteins, including Smad2, Smad3, Smad4, and Smad7, and that this association is mediated by the pleckstrin homology domain of PDK1. |
| GO:0010718 positive regulation of epithelial to mesenchymal transition | IMP PMID:18505915 Transforming growth factor-beta1, transforming growth factor... | KEEP AS NON CORE | Summary: Positive regulation of EMT (PMID:18505915). Reason: Valid downstream effect. TGF-beta/SMAD3 is a major driver of EMT. Non-core but well-documented process. Supporting Evidence: |
| GO:0045216 cell-cell junction organization | IMP PMID:18505915 Transforming growth factor-beta1, transforming growth factor... | KEEP AS NON CORE | Summary: Cell-cell junction organization (PMID:18505915). Related to EMT. Reason: Valid downstream effect related to TGF-beta-induced EMT. Non-core pleiotropic process. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:16200078 Cloning and functional characterization of a new Ski homolog... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0005515 protein binding | IPI PMID:17292623 Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP ... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0070410 co-SMAD binding | IPI PMID:8774881 Receptor-associated Mad homologues synergize as effectors of... | ACCEPT | Summary: SMAD3 binds the co-SMAD SMAD4 during receptor-regulated complex assembly. Cellular interaction studies and the phosphorylated SMAD3-SMAD4 heterotrimer structure directly support this core interaction. Reason: SMAD3 binds the co-SMAD SMAD4 during receptor-regulated complex assembly. Cellular interaction studies and the phosphorylated SMAD3-SMAD4 heterotrimer structure directly support this core interaction. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15350224 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. |
| GO:0070410 co-SMAD binding | IPI PMID:9111321 Heteromeric and homomeric interactions correlate with signal... | ACCEPT | Summary: SMAD3 binds the co-SMAD SMAD4 during receptor-regulated complex assembly. Cellular interaction studies and the phosphorylated SMAD3-SMAD4 heterotrimer structure directly support this core interaction. Reason: SMAD3 binds the co-SMAD SMAD4 during receptor-regulated complex assembly. Cellular interaction studies and the phosphorylated SMAD3-SMAD4 heterotrimer structure directly support this core interaction. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15350224 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. |
| GO:0070410 co-SMAD binding | IPI PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: SMAD3 binds the co-SMAD SMAD4 during receptor-regulated complex assembly. Cellular interaction studies and the phosphorylated SMAD3-SMAD4 heterotrimer structure directly support this core interaction. Reason: SMAD3 binds the co-SMAD SMAD4 during receptor-regulated complex assembly. Cellular interaction studies and the phosphorylated SMAD3-SMAD4 heterotrimer structure directly support this core interaction. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15350224 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. |
| GO:0070410 co-SMAD binding | IPI PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | ACCEPT | Summary: SMAD3 binds the co-SMAD SMAD4 during receptor-regulated complex assembly. Cellular interaction studies and the phosphorylated SMAD3-SMAD4 heterotrimer structure directly support this core interaction. Reason: SMAD3 binds the co-SMAD SMAD4 during receptor-regulated complex assembly. Cellular interaction studies and the phosphorylated SMAD3-SMAD4 heterotrimer structure directly support this core interaction. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. PMID:15350224 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. |
| GO:0070412 R-SMAD binding | IPI PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: SMAD3 forms complexes with receptor-regulated SMAD proteins, including SMAD2, as shown by the TGF-beta-induced interaction study. PMID:20129061 studies TMEPAI binding to R-SMADs; the independent SMAD-complex study is used here to support SMAD3 itself as the binder. Reason: SMAD3 forms complexes with receptor-regulated SMAD proteins, including SMAD2, as shown by the TGF-beta-induced interaction study. PMID:20129061 studies TMEPAI binding to R-SMADs; the independent SMAD-complex study is used here to support SMAD3 itself as the binder. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | MODIFY | Summary: SMAD3 recognizes regulatory DNA sequences at RNA polymerase II target genes; refine the general cis-regulatory binding term to the supported sequence-specific term already present. Reason: SMAD3 recognizes regulatory DNA sequences at RNA polymerase II target genes; refine the general cis-regulatory binding term to the supported sequence-specific term already present. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:9732876 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. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | MODIFY | Summary: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Reason: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0007179 transforming growth factor beta receptor signaling pathway | IDA PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | ACCEPT | Summary: TGF-beta receptor signaling pathway confirmed (PMID:9732876). Reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling. Supporting Evidence: PMID:9732876 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. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | MODIFY | Summary: The transcriptional activation assays concern RNA polymerase II genes, so the existing polymerase-specific positive regulation term is more precise. Reason: The transcriptional activation assays concern RNA polymerase II genes, so the existing polymerase-specific positive regulation term is more precise. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9732876 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. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:9111321 Heteromeric and homomeric interactions correlate with signal... | MODIFY | Summary: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Reason: SMAD3 regulates RNA polymerase II target genes. Refine the general DNA-binding transcription factor term to the supported polymerase-specific activity already asserted here. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:9732876 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:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0005160 transforming growth factor beta receptor binding | IPI PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: SMAD3 binds the TGF-beta type I receptor. Nakao et al. (1997) showed that Smad3 interacted with the kinase-deficient TGF-beta type I receptor after it was phosphorylated by TbetaR-II kinase (PMID:9311995). Reason: Core molecular function. SMAD3 physically interacts with the activated TGF-beta type I receptor (ALK5/TGFBR1) as an essential step in signal transduction. This interaction is required for SMAD3 phosphorylation and pathway activation. Supporting Evidence: PMID:9311995 Smad2 and Smad3 interacted with the kinase-deficient TGF-beta type I receptor (TbetaR)-I after it was phosphorylated by TbetaR-II kinase. |
| GO:0005634 nucleus | IDA PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: Nucleus localization confirmed (PMID:9311995). SMAD3 translocates to nucleus upon TGF-beta activation. Reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0005737 cytoplasm | IDA PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: Cytoplasm localization confirmed (PMID:9311995). SMAD3 resides in cytoplasm before activation. Reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus. Supporting Evidence: PMID:9311995 These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction. |
| GO:0031053 primary miRNA processing | TAS PMID:19018011 Holding their own: the noncanonical roles of Smad proteins. | KEEP AS NON CORE | Summary: SMAD3 participates in primary microRNA processing through association with the DDX5/p68-DROSHA complex; primary experiments provide support beyond the review cited in the seeded row. This is a secondary SMAD4-independent response, not simply transcription of a miRNA gene. Reason: SMAD3 participates in primary microRNA processing through association with the DDX5/p68-DROSHA complex; primary experiments provide support beyond the review cited in the seeded row. This is a secondary SMAD4-independent response, not simply transcription of a miRNA gene. Supporting Evidence: PMID:18548003 TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. |
| GO:0042060 wound healing | TAS PMID:19018011 Holding their own: the noncanonical roles of Smad proteins. | KEEP AS NON CORE | Summary: SMAD3 participates in wound healing through TGF-beta signaling. TGF-beta/SMAD3 signaling is a major regulator of wound healing and fibrosis responses (PMID:19018011). Reason: Valid downstream biological outcome of TGF-beta/SMAD3 signaling. Wound healing is a well-known physiological context in which TGF-beta/SMAD3 signaling plays a role, but represents a tissue-level process rather than a core molecular or signaling function. Supporting Evidence: |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9111321 Heteromeric and homomeric interactions correlate with signal... | MODIFY | Summary: The transcriptional activation assays concern RNA polymerase II genes, so the existing polymerase-specific positive regulation term is more precise. Reason: The transcriptional activation assays concern RNA polymerase II genes, so the existing polymerase-specific positive regulation term is more precise. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9732876 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. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | MODIFY | Summary: The transcriptional activation assays concern RNA polymerase II genes, so the existing polymerase-specific positive regulation term is more precise. Reason: The transcriptional activation assays concern RNA polymerase II genes, so the existing polymerase-specific positive regulation term is more precise. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9732876 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. |
| GO:0005515 protein binding | IPI PMID:19122240 Pin1 down-regulates transforming growth factor-beta (TGF-bet... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19122240 Pin1 down-regulates transforming growth factor-beta (TGF-bet... | KEEP AS NON CORE | Summary: Binding to E3 ubiquitin ligases regulates SMAD3 ubiquitination, turnover and signaling duration. CHIP and Smurf2 studies support this interaction independently of the broader Smurf1/Smad7 focus of PMID:11278251. This is a regulatory interaction rather than SMAD3 catalytic ubiquitin-ligase activity. Reason: Binding to E3 ubiquitin ligases regulates SMAD3 ubiquitination, turnover and signaling duration. CHIP and Smurf2 studies support this interaction independently of the broader Smurf1/Smad7 focus of PMID:11278251. This is a regulatory interaction rather than SMAD3 catalytic ubiquitin-ligase activity. Supporting Evidence: PMID:15781469 Finally, we demonstrated that CHIP served as a U-box dependent E3 ligase that can directly mediate ubiquitination and degradation of Smad3 and that this action of CHIP was independent of TGF-beta signaling. PMID:19122240 Pin1 interacted with Smad2 and Smad3 but not Smad4; this interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region. (S/T)P motif phosphorylation also enhanced the interaction of Smad2/3 with Smurf2. |
| GO:0006955 immune response | IMP PMID:16886151 Association of polymorphisms of IGF1R and genes in the trans... | KEEP AS NON CORE | Summary: SMAD3-dependent immunoregulation is supported by IL-37 functional studies and Smad3-mutant mice. The attached PMID:16886151 is a genetic association study of bacteremia susceptibility and does not by itself establish the molecular immune mechanism. Reason: SMAD3-dependent immunoregulation is supported by IL-37 functional studies and Smad3-mutant mice. The attached PMID:16886151 is a genetic association study of bacteremia susceptibility and does not by itself establish the molecular immune mechanism. Supporting Evidence: PMID:10064594 Mutant T cells exhibit an activated phenotype in vivo, and are not inhibited by TGF-beta1 in vitro. |
| GO:0005515 protein binding | IPI PMID:11274402 Inactivation of menin, a Smad3-interacting protein, blocks t... | REMOVE | Summary: The seeded study reports a protein interaction involving SMAD3, but the bare protein-binding term does not specify a biological activity. Reason: Remove the uninformative protein-binding annotation under repository policy. This does not reject the reported interaction or infer that the partner was not assayed. Specific SMAD, receptor, transcriptional-partner and enzyme-binding activities are assessed separately where supported. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:14555988 Differential regulation of TGF-beta signaling through Smad2,... | ACCEPT | Summary: SMAD3 represses transcription of specific target genes in the TGF-beta pathway. Differential regulation through SMAD2, SMAD3 and SMAD4 has been demonstrated, with SMAD3 contributing to transcriptional repression at specific promoters (PMID:14555988). Reason: Core transcriptional function. SMAD3 acts as both a transcriptional activator and repressor depending on the target gene and cofactor context. At repressive loci, SMAD3 recruits co-repressors such as Ski/SnoN/TGIF to silence gene expression. This is consistent with other annotations for this GO term already accepted with IDA evidence. Supporting Evidence: PMID:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:8774881 Receptor-associated Mad homologues synergize as effectors of... | ACCEPT | Summary: Negative regulation of transcription by Pol II confirmed (PMID:8774881). SMAD3 can repress transcription. Reason: Valid. SMAD3 acts as transcriptional repressor at certain loci with Ski/SnoN/TGIF cofactors. Supporting Evidence: PMID:32141990 Smad3 bound to the promoter of miR-4286 to repress its transcription. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:8774881 Receptor-associated Mad homologues synergize as effectors of... | ACCEPT | Summary: Positive regulation of Pol II transcription confirmed (PMID:8774881). Reason: Core biological process. SMAD3 activates transcription of TGF-beta responsive genes. Supporting Evidence: |
| GO:0001666 response to hypoxia | IMP PMID:12411310 Cellular response to hypoxia involves signaling via Smad pro... | KEEP AS NON CORE | Summary: Cellular response to hypoxia involves signaling via Smad proteins including SMAD3 (PMID:12411310). Hypoxia activates TGF-beta/SMAD signaling, with SMAD3 acting as a mediator of hypoxia-induced gene expression changes. Reason: Valid annotation supported by IMP evidence, but represents a stimulus-response context for SMAD3 signaling rather than a core function. SMAD3 mediates responses to hypoxia through its role in TGF-beta signaling, but hypoxia response is not a primary function of SMAD3. Supporting Evidence: |
| GO:0032909 regulation of transforming growth factor beta2 production | IMP PMID:12411310 Cellular response to hypoxia involves signaling via Smad pro... | KEEP AS NON CORE | Summary: SMAD3 participates in regulation of TGF-beta2 production (PMID:12411310). This represents a feedback mechanism within the TGF-beta signaling pathway, where SMAD3-dependent transcription influences production of TGF-beta2 ligand. Reason: Valid annotation representing a downstream transcriptional outcome of SMAD3 signaling. Regulation of TGF-beta2 production is a specific transcriptional target/feedback mechanism rather than a core function. SMAD3 regulates many target genes; this is one pathway-specific output. Supporting Evidence: |
| GO:0005634 nucleus | IDA PMID:12446380 TGFbeta-Smad signalling in postoperative human lens epitheli... | ACCEPT | Summary: Nucleus localization confirmed (PMID:12446380). SMAD3 translocates to nucleus upon TGF-beta activation. Reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:12446380 TGFbeta-Smad signalling in postoperative human lens epitheli... | ACCEPT | Summary: Cytoplasm localization confirmed (PMID:12446380). SMAD3 resides in cytoplasm before activation. Reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus. Supporting Evidence: |
| GO:0030308 negative regulation of cell growth | IDA PMID:8774881 Receptor-associated Mad homologues synergize as effectors of... | KEEP AS NON CORE | Summary: SMAD3 mediates TGF-beta-induced growth inhibition. Zhang et al. (1996) demonstrated that hMAD-3 (SMAD3) and hMAD-4 (SMAD4) synergize to induce TGF-beta-like responses including growth arrest, and that C-terminally truncated forms act as dominant-negative inhibitors of normal TGF-beta response (PMID:8774881). Reason: Well-supported by early functional studies. TGF-beta-induced growth inhibition is a major biological outcome of SMAD3 signaling, but is a downstream cellular response rather than a core molecular or signaling function. SMAD3 mediates this through transcriptional regulation of cell cycle inhibitors like p15INK4b and p21. Supporting Evidence: PMID:8774881 hMAD-3 and -4 synergized to induce strong ligand-independent TGF-beta-like responses. When truncated at their carboxy termini, hMAD-3 and -4 act as dominant-negative inhibitors of the normal TGF-beta response. |
| GO:0042803 protein homodimerization activity | IPI PMID:8774881 Receptor-associated Mad homologues synergize as effectors of... | UNDECIDED | Summary: SMAD3 self-association is established, but the precise homodimer stoichiometry is not resolved from the accessible source. Reason: The primary interaction studies establish homomeric association, while structural work describes R-SMAD homotrimers and heterotrimers. Neither observation alone settles the more specific homodimerization assertion. Keep identical protein binding accepted and leave this experimental stoichiometric claim unresolved rather than overrule it from an abstract. Supporting Evidence: PMID:9111321 We now show that Smad3 and Smad4 associate in homomeric and heteromeric interactions, as assessed by yeast two-hybrid and coimmunoprecipitation analyses. PMID:15350224 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. |
| GO:0043235 receptor complex | IMP PMID:8774881 Receptor-associated Mad homologues synergize as effectors of... | KEEP AS NON CORE | Summary: SMAD3 transiently associates with the TGF-beta receptor complex. Zhang et al. (1996) showed that hMAD-3 (SMAD3) was phosphorylated and associated with the ligand-bound receptor complex (PMID:8774881). Nakao et al. (1997) confirmed that SMAD3 interacts with the activated TGF-beta type I receptor (PMID:9311995). Reason: Valid but SMAD3 is not a permanent constituent of the receptor complex. SMAD3 transiently associates with the activated TGF-beta type I receptor for phosphorylation and then dissociates. The primary localization of SMAD3 is cytoplasm (basal) and nucleus (activated). This CC annotation is technically correct but could be misleading about stable residency. Supporting Evidence: PMID:8774881 hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:10823886 Transforming growth factor beta -inducible independent bindi... | MODIFY | Summary: The established sequence-specific DNA-binding activity is at transcriptional regulatory elements; refine to the existing RNA polymerase II cis-regulatory region term. Reason: The established sequence-specific DNA-binding activity is at transcriptional regulatory elements; refine to the existing RNA polymerase II cis-regulatory region term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:9732876 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. |
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