SMAD3 (Mothers against decapentaplegic homolog 3) is a receptor-regulated SMAD (R-SMAD) that serves as the principal intracellular signal transducer and transcriptional modulator in the TGF-beta/activin signaling pathway. Upon TGF-beta receptor activation, SMAD3 is phosphorylated at its C-terminal SSXS motif by TGF-beta type I receptor (ALK5/TGFBR1), forms heteromeric complexes with SMAD4 (co-SMAD), and translocates to the nucleus where it directly binds DNA at SMAD binding elements (SBE: GTCT/AGAC) and CAGA-box variants through its MH1 domain. SMAD3 cooperates with transcription factors such as c-Jun/c-Fos at composite AP-1/SMAD elements. It also participates in activin and nodal signaling. Key biological outcomes include regulation of cell proliferation, EMT, fibrosis, immune regulation, and cell differentiation. Germline mutations cause Loeys-Dietz syndrome type 3.
| 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 DNA at SMAD binding elements (SBEs) in cis-regulatory regions of target genes, demonstrated by crystal structure (PMID:9741623), CASTing assays (Itoh et al. 2024), and ChIP-seq studies. IBA is well-supported across SMAD family. Reason: Core molecular function of SMAD3. The MH1 domain directly binds SBE sequences (GTCT/AGAC) in promoter/enhancer regions, extensively validated by structural and functional studies. 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. PMID:9732876 Smad3 interacts directly with the TRE and that Smad3 and Smad4 can activate TGF-beta-inducible transcription from the TRE |
| GO:0009653 anatomical structure morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SMAD3 is involved in anatomical structure morphogenesis via TGF-beta signaling. IBA supported across species. Reason: This is a broad downstream biological process. While SMAD3 contributes to morphogenesis through TGF-beta signaling, this is a pleiotropic outcome rather than a core function. IBA is valid at this level for SMAD family. |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SMAD3 is involved in cell differentiation through TGF-beta signaling. IBA supported. Reason: Broad downstream process. TGF-beta/SMAD3 signaling regulates differentiation in many contexts (chondrocyte, osteoblast, T cell, etc.), but this is a pleiotropic outcome rather than core function. |
| GO:0032924 activin receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD3 also mediates activin receptor signaling, being phosphorylated by ACVR1B. IBA well-supported. Reason: Core biological process. SMAD3 is activated by activin type I receptor (ACVR1B/ALK4) in addition to TGF-beta receptors. UniProt confirms interaction with ACVR1B (PMID:9892009). Supporting Evidence: PMID:9892009 Roles of pathway-specific and inhibitory Smads in activin receptor signaling |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: SMAD3 is a sequence-specific DNA-binding transcription factor that activates and represses RNA polymerase II target genes in response to TGF-beta signaling. IBA supported across the SMAD family. Reason: Core molecular function. SMAD3 directly binds DNA through its MH1 domain and recruits transcriptional coactivators (p300/CBP) or corepressors (Ski/SnoN, TGIF) to regulate Pol II transcription. Supporting Evidence: PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription PMID:21947082 USP15 is required for TGFbeta and BMP responses in mammalian cells |
| 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 |
| 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: SMAD3 forms heteromeric SMAD complexes with SMAD4 upon TGF-beta stimulation. IBA well-supported across species. Reason: Core cellular component. The SMAD3/SMAD4 heteromeric complex is the functional unit of TGF-beta signaling. Crystal structure solved (PMID:15350224). Supporting Evidence: PMID:9311995 TGF-beta induces heteromeric complexes of Smads 2, 3 and 4 |
| 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: SMAD3 binds inhibitory SMADs (SMAD6/SMAD7). IBA supported across the SMAD family. Reason: Well-established interaction. Inhibitory SMADs compete with R-SMADs for receptor binding and recruit phosphatases/ubiquitin ligases. SMAD3 binds SMAD7 as part of pathway regulation. |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for DNA binding. SMAD3 directly binds DNA through MH1 domain at SBE sequences. Reason: Correct but overly broad. More specific DNA binding terms (GO:0000978, GO:0000987) are already annotated with experimental evidence. This IEA is acceptable as a general parent term. |
| 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. |
| 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). |
| 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. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for regulation of DNA-templated transcription based on InterPro domain mapping. Reason: Correct. SMAD3 is a transcription factor that regulates DNA-templated transcription. Consistent with experimental annotations. |
| GO:0032502 developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IEA for developmental process. Very broad term from ARBA prediction. Reason: Excessively broad. While TGF-beta/SMAD3 signaling contributes to development, GO:0032502 is too general to be informative. More specific developmental processes are annotated elsewhere. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: IEA for metal ion binding from UniProt keyword mapping. SMAD3 MH1 domain coordinates a zinc ion essential for DNA binding. Reason: The annotation is correct in that SMAD3 binds metal ions, but the term is too broad. The MH1 domain contains a zinc-binding site essential for structural integrity and DNA binding (PMID:12686552). Should be zinc ion binding (GO:0008270) which is already annotated with IDA. Proposed replacements: zinc ion binding |
| GO:0071363 cellular response to growth factor stimulus | IEA GO_REF:0000117 | ACCEPT | Summary: IEA for cellular response to growth factor stimulus. SMAD3 mediates TGF-beta responses. Reason: Correct but broad. SMAD3 mediates cellular responses to TGF-beta and activin, which are growth factors. More specific pathway terms are also annotated. |
| GO:0141091 transforming growth factor beta receptor superfamily signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: IEA for TGF-beta receptor superfamily signaling pathway from ARBA. Reason: Correct. SMAD3 is a core mediator of TGF-beta receptor superfamily signaling. More specific TGF-beta pathway terms are also present. |
| GO:0005515 protein binding | IPI PMID:11278756 Ski-interacting protein interacts with Smad proteins to augm... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:11278756). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:11387212 The adaptor molecule Disabled-2 links the transforming growt... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:11387212). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:12154125 Smad3 allostery links TGF-beta receptor kinase activation to... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:12154125). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:12650946 Identification of three novel Smad binding proteins involved... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:12650946). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:12857746 Direct interaction of Ski with either Smad3 or Smad4 is nece... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:12857746). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:14525983 DACH1 inhibits transforming growth factor-beta signaling thr... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:14525983). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:15084259 Integration of Smad and forkhead pathways in the control of ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15084259). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:15231748 Functional proteomics mapping of a human signaling pathway. | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15231748). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:15350224 Structural basis of heteromeric smad protein assembly in TGF... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15350224). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:15527767 Proteomics-based identification of proteins interacting with... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15527767). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:16007207 Hepatitis C virus core variants isolated from liver tumor bu... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:16007207). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:17785517 Msk is required for nuclear import of TGF-{beta}/BMP-activat... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:17785517). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:18548003 SMAD proteins control DROSHA-mediated microRNA maturation. | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:18548003). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:18729074 Identification of novel Smad2 and Smad3 associated proteins ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:18729074). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:19032343 Ski co-repressor complexes maintain the basal repressed stat... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19032343). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:19135894 FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta s... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19135894). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:20061380 MTMR4 attenuates transforming growth factor beta (TGFbeta) s... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:20061380). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:20211142). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:21258410 Selective targeting of activating and inhibitory Smads by di... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21258410). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:21297662 Homeodomain protein DLX4 counteracts key transcriptional con... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21297662). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:21532621 Nodal enhances the activity of FoxO3a and its synergistic in... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21532621). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:21597466 Antagonistic regulation of EMT by TIF1Ξ³ and Smad4 in mammary... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21597466). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:21828274 HEB and E2A function as SMAD/FOXH1 cofactors. | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21828274). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21988832). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:22045334 Ablation of Smurf2 reveals an inhibition in TGF-Ξ² signalling... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:22045334). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:22442258 Intercellular variation in signaling through the TGF-Ξ² pathw... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:22442258). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:22538441 CSMD1 exhibits antitumor activity in A375 melanoma cells thr... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:22538441). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25416956). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25502805). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25609649). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:25670079 14-3-3ΞΆ turns TGF-Ξ²'s function from tumor suppressor to meta... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25670079). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25910212). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:26680585 ShcA Protects against Epithelial-Mesenchymal Transition thro... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:26680585). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:27107012). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:28471448 MiR-1 suppresses tumor cell proliferation in colorectal canc... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:28471448). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:29892012). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:29997244). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:31515488). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:32296183). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:32814053). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:33961781). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:35512704). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:39243984 Gain-of-function variants in SMAD4 compromise respiratory ep... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:39243984). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0042802 identical protein binding | IPI PMID:18729074 Identification of novel Smad2 and Smad3 associated proteins ... | ACCEPT | Summary: SMAD3 forms homo-oligomers. Confirmed by co-immunoprecipitation and structural studies. Reason: SMAD3 homo-oligomerization is well-documented. Crystal structure shows SMAD3 trimeric assembly (PMID:11224571). Supporting Evidence: PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. |
| GO:0042802 identical protein binding | IPI PMID:22045334 Ablation of Smurf2 reveals an inhibition in TGF-Ξ² signalling... | ACCEPT | Summary: SMAD3 forms homo-oligomers. Confirmed by co-immunoprecipitation and structural studies. Reason: SMAD3 homo-oligomerization is well-documented. Crystal structure shows SMAD3 trimeric assembly (PMID:11224571). Supporting Evidence: PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. |
| 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). |
| GO:0000165 MAPK cascade | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for MAPK cascade. Reason: SMAD3 is not a core component of the MAPK cascade. While MAPK phosphorylates SMAD3 linker region, and SMAD3/AP-1 cooperate at promoters, SMAD3 does not directly participate in the MAPK cascade itself. Cross-talk annotation is misleading. |
| 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. |
| 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. |
| GO:0001649 osteoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for osteoblast differentiation from mouse data. Reason: Valid downstream effect. SMAD3 regulates osteoblast differentiation and chondrogenesis (UniProt confirms SMAD3 is a regulator of osteogenesis). Non-core pleiotropic process. |
| GO:0001657 ureteric bud development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for ureteric bud development from mouse data. Reason: Very specific developmental process likely reflecting pleiotropic TGF-beta pathway effects in kidney development. No direct evidence for SMAD3-specific role in ureteric bud development in humans. |
| GO:0001836 release of cytochrome c from mitochondria | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for release of cytochrome c from mitochondria from rat data. Reason: Indirect downstream effect. TGF-beta/SMAD3 signaling can trigger apoptosis in some contexts, which may involve cytochrome c release, but this is not a direct function of SMAD3. |
| 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). |
| GO:0003690 double-stranded DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for double-stranded DNA binding from mouse data. Reason: Correct. Crystal structure confirms SMAD3 MH1 domain binds dsDNA at SBE sequences (PMID:9741623, PMID:12686552). |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for DNA-binding transcription factor activity. Reason: Correct. SMAD3 is a bona fide DNA-binding transcription factor. Also supported by multiple IDA annotations. |
| GO:0005518 collagen binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for collagen binding from mouse data. Reason: SMAD3 regulates collagen gene expression as a transcription factor, but there is no evidence it directly binds collagen protein. This appears to be a misannotation or conflation of transcriptional regulation with physical binding. |
| 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. |
| 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. |
| GO:0007254 JNK cascade | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for JNK cascade from mouse data. Reason: SMAD3 is not a component of the JNK cascade. While TGF-beta can activate JNK through non-canonical signaling and SMAD3/JUN cooperate at AP-1 sites, SMAD3 does not participate directly in JNK signal transduction. |
| GO:0008013 beta-catenin binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA annotation for beta-catenin binding via Ensembl Compara ortholog transfer. SMAD3 has been reported to interact with beta-catenin in the context of Wnt/TGF-beta crosstalk, but this is not a primary binding activity. Reason: While SMAD3 can interact with beta-catenin in certain cellular contexts as part of Wnt/TGF-beta signaling crosstalk, beta-catenin binding is not a core molecular function of SMAD3. This IEA annotation likely represents a context-dependent interaction rather than an intrinsic binding activity. |
| 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. |
| GO:0010332 response to gamma radiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for response to gamma radiation from rat data. Reason: Indirect response. While SMAD3 may be activated or its expression altered by gamma radiation in some cell types, this is not a direct or core function of SMAD3. |
| GO:0010467 gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for gene expression from mouse data. Reason: Excessively broad. 'Gene expression' is too general. SMAD3 regulates transcription, which is a component of gene expression, but more specific terms are already annotated. |
| GO:0019899 enzyme binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for enzyme binding from rat data. Reason: While SMAD3 binds kinases (TGFBR1, CDKs, PDPK1), phosphatases (PPM1A), and E3 ligases, 'enzyme binding' is too broad. More specific binding terms are already present. |
| 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. |
| GO:0030325 adrenal gland development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for adrenal gland development from rat data. Reason: Very specific developmental process likely reflecting broad TGF-beta pathway pleiotropic effects. No direct evidence for SMAD3-specific role in human adrenal development. |
| GO:0030335 positive regulation of cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for positive regulation of cell migration from rat data. Reason: Valid downstream effect. TGF-beta/SMAD3 signaling promotes cell migration, particularly in EMT context. UniProt notes SMAD3 role in EMT. Non-core pleiotropic process. |
| GO:0030501 positive regulation of bone mineralization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for positive regulation of bone mineralization from rat data. Reason: Valid downstream effect. UniProt notes SMAD3 is a regulator of osteogenesis. Non-core tissue-specific process. |
| 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. |
| GO:0032332 positive regulation of chondrocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for positive regulation of chondrocyte differentiation from mouse data. Reason: Valid downstream effect. UniProt notes SMAD3 is a regulator of chondrogenesis. Non-core developmental process. |
| GO:0032731 positive regulation of interleukin-1 beta production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for positive regulation of IL-1 beta production from rat data. Reason: Indirect downstream effect of TGF-beta signaling in immune regulation. Not a direct function of SMAD3 as a transcription factor. |
| GO:0032916 positive regulation of transforming growth factor beta3 production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for positive regulation of TGF-beta3 production from rat data. Reason: While SMAD3 could transcriptionally regulate TGF-beta3 expression as a feedback mechanism, this is a very specific downstream effect. Limited direct human evidence. |
| 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). |
| GO:0033689 negative regulation of osteoblast proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for negative regulation of osteoblast proliferation from mouse data. Reason: Valid downstream effect consistent with SMAD3 role in osteogenesis regulation. Non-core tissue-specific process. |
| GO:0036120 cellular response to platelet-derived growth factor stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for cellular response to PDGF stimulus from rat data. Reason: Indirect. PDGF may modulate TGF-beta/SMAD signaling through MAPK crosstalk, but SMAD3 is not a direct mediator of PDGF responses. |
| GO:0042110 T cell activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for T cell activation from mouse data. Reason: Valid downstream effect. TGF-beta/SMAD3 signaling is critical for T cell differentiation and immune regulation. SMAD3 knockout mice have T cell activation defects. Non-core immune process. |
| GO:0042177 negative regulation of protein catabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for negative regulation of protein catabolic process from rat data. Reason: Indirect downstream effect. While TGF-beta signaling can affect protein stability, this is not a direct SMAD3 function. |
| GO:0042220 response to cocaine | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for response to cocaine from rat data. Reason: Highly specific environmental response likely from rat neurological studies. No evidence SMAD3 directly mediates cocaine responses. Over-annotation from ortholog transfer. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for identical protein binding from mouse data. Reason: Correct. SMAD3 forms homomeric complexes. SMAD3 homo-oligomerization is well-documented (PMID:9670020). |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for negative regulation of apoptotic process from rat data. Reason: Context-dependent downstream effect. TGF-beta/SMAD3 can both promote and inhibit apoptosis depending on cell type. Non-core pleiotropic process. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl orthologs) for sequence-specific DNA binding from rat data. Reason: Correct. SMAD3 MH1 domain binds specific DNA sequences (SBE: GTCT/AGAC). Crystal structure confirms sequence-specific binding (PMID:9741623). |
| 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. |
| 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. |
| 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. |
| GO:0050776 regulation of immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for regulation of immune response from mouse data. Reason: Valid broad downstream effect. TGF-beta/SMAD3 is critical for immune regulation. Non-core pleiotropic process. |
| GO:0050821 protein stabilization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for protein stabilization from rat data. Reason: Indirect effect. While SMAD3 can affect protein stability through transcriptional regulation of ubiquitin pathway components, protein stabilization is not a direct function. |
| GO:0050927 positive regulation of positive chemotaxis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for positive regulation of positive chemotaxis from rat data. Reason: Indirect downstream effect of TGF-beta signaling. Not a direct SMAD3 function. |
| GO:0051496 positive regulation of stress fiber assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for positive regulation of stress fiber assembly from rat data. Reason: Indirect downstream effect. TGF-beta can promote stress fiber formation through EMT-related cytoskeletal remodeling, but this is not a direct SMAD3 transcription factor function. |
| GO:0051881 regulation of mitochondrial membrane potential | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for regulation of mitochondrial membrane potential from rat data. Reason: Indirect downstream effect. Not a direct function of SMAD3 as a transcription factor. |
| GO:0051894 positive regulation of focal adhesion assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for positive regulation of focal adhesion assembly from rat data. Reason: Indirect downstream effect of TGF-beta-mediated EMT or cytoskeletal changes. Not a direct SMAD3 function. |
| GO:0060290 transdifferentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for transdifferentiation from rat data. Reason: Valid downstream effect. TGF-beta/SMAD3 drives EMT (a form of transdifferentiation). Non-core pleiotropic process. |
| 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. |
| GO:0061001 regulation of dendritic spine morphogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for regulation of dendritic spine morphogenesis from rat data. Reason: Very specific neuronal process. Likely indirect TGF-beta pathway effect. No direct evidence for SMAD3-specific role in dendritic spine morphogenesis in humans. |
| 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. |
| 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. |
| GO:0061767 negative regulation of lung blood pressure | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for negative regulation of lung blood pressure from rat data. Reason: Very specific physiological process likely from rat cardiovascular studies. Indirect downstream effect of TGF-beta signaling. |
| GO:0071333 cellular response to glucose stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for cellular response to glucose stimulus from rat data. Reason: Indirect. TGF-beta/SMAD signaling may be modulated by metabolic conditions, but SMAD3 is not a direct glucose sensor. |
| 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). |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for positive regulation of canonical Wnt signaling pathway from rat data. Reason: SMAD3 is not a direct component of the Wnt pathway. While there is TGF-beta/Wnt pathway crosstalk, annotating SMAD3 to Wnt pathway regulation is misleading. |
| 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. |
| GO:0097305 response to alcohol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for response to alcohol from rat data. Reason: Likely from rat liver/fibrosis studies where alcohol induces TGF-beta signaling. Not a direct SMAD3 function. |
| GO:0098586 cellular response to virus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl orthologs) for cellular response to virus from mouse data. Reason: TGF-beta/SMAD3 signaling is involved in antiviral responses and immune regulation. SARS-CoV nucleoprotein interacts with SMAD3 (PMID:18055455). Non-core immune process. |
| GO:1903243 negative regulation of cardiac muscle hypertrophy in response to stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA (Ensembl orthologs) for negative regulation of cardiac muscle hypertrophy from rat data. Reason: Very specific cardiac process. Indirect TGF-beta pathway effect. Not a direct SMAD3 function. |
| 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. |
| 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. |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:35359452 The Interplay Between TGF-Ξ² Signaling and Cell Metabolism. | ACCEPT | Summary: Regulation of DNA-templated transcription confirmed (PMID:35359452). Reason: Core biological process. SMAD3 is a transcription factor that regulates gene expression. |
| 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. |
| GO:0032924 activin receptor signaling pathway | NAS PMID:15150278 Nodal and ALK7 inhibit proliferation and induce apoptosis in... | ACCEPT | Summary: Activin receptor signaling pathway confirmed (PMID:15150278). Reason: Core biological process. SMAD3 mediates activin signaling through ACVR1B. |
| 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. |
| 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. |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:25060702 A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent... | ACCEPT | Summary: Regulation of DNA-templated transcription confirmed (PMID:25060702). Reason: Core biological process. SMAD3 is a transcription factor that regulates gene expression. |
| 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. |
| 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. |
| GO:0071635 negative regulation of transforming growth factor beta production | NAS PMID:20935647 IL-37 is a fundamental inhibitor of innate immunity. | KEEP AS NON CORE | Summary: Negative regulation of TGF-beta production (PMID:20935647). NAS from ComplexPortal. Reason: Valid feedback regulation. SMAD3 can modulate TGF-beta expression as part of signaling feedback. Non-core regulatory process. |
| 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. |
| 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. |
| GO:0060391 positive regulation of SMAD protein signal transduction | IMP PMID:15107418 Activin receptor-like kinase-7 induces apoptosis through act... | ACCEPT | Summary: Positive regulation of SMAD protein signal transduction (PMID:15107418). Reason: SMAD3 positively promotes SMAD signal transduction as an R-SMAD that forms complexes with SMAD4. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:15781469 CHIP controls the sensitivity of transforming growth factor-... | ACCEPT | Summary: Ubiquitin protein ligase binding confirmed. SMAD3 interacts with E3 ligases including SMURF2, NEDD4L, STUB1/CHIP (PMID:15781469). Reason: Well-supported. SMAD3 is a substrate of multiple E3 ubiquitin ligases that regulate its stability and function. |
| 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. |
| 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. |
| 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. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:10823886 Transforming growth factor beta -inducible independent bindi... | ACCEPT | Summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:10823886). Reason: Core molecular function of SMAD3. Directly binds DNA and regulates 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. |
| 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. |
| 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. |
| 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. |
| GO:0003700 DNA-binding transcription factor activity | IMP PMID:32141990 miR-4286/TGF-Ξ²1/Smad3-Negative Feedback Loop Ameliorated Vas... | ACCEPT | Summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:32141990). Reason: Core molecular function of SMAD3. Directly binds DNA and regulates 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. |
| 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: RNA polymerase II cis-regulatory region sequence-specific DNA binding confirmed (PMID:24378993). Reason: Core molecular function. SMAD3 binds SBEs in Pol II-regulated cis-regulatory regions. |
| 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. |
| 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. |
| GO:0010629 negative regulation of gene expression | IMP PMID:24378993 Crosstalk between TGF-Ξ²/Smad3 and BMP/BMPR2 signaling pathwa... | ACCEPT | Summary: Negative regulation of gene expression (PMID:24378993). Reason: Valid. SMAD3 can repress gene expression at certain loci through corepressor recruitment. |
| 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. |
| 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. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2179276 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2179276). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005515 protein binding | IPI PMID:15051726 Atrophin-1-interacting protein 4/human Itch is a ubiquitin E... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15051726). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:29899023 NEDD9 targets COL3A1 to promote endothelial fibrosis and pul... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:29899023). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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: Core molecular function. SMAD3 activates transcription of TGF-beta target genes. |
| 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: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:25605017). Reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes. |
| GO:0032810 sterol response element binding | IGI PMID:25605017 Reduction of miR-29c enhances pancreatic cancer cell migrati... | KEEP AS NON CORE | Summary: Sterol response element binding. SMAD3 binds SRE in IGI with TGF-beta1 (PMID:25605017). Reason: Specialized binding activity at specific genomic loci. Non-core but documented. |
| 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. | ACCEPT | Summary: DNA-binding transcription factor binding. SMAD3 binds FOXH1 (PMID:21828274). Reason: Well-supported. SMAD3 cooperates with multiple DNA-binding TFs. |
| GO:0016922 nuclear receptor binding | IPI PMID:31023188 LRP1 Deficiency in Vascular SMC Leads to Pulmonary Arterial ... | ACCEPT | Summary: Nuclear receptor binding. SMAD3 binds PPARgamma (PMID:31023188). Reason: Well-documented interaction. SMAD3 interacts with nuclear receptors as part of transcriptional cross-talk. |
| 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. |
| GO:1902893 regulation of miRNA transcription | IC PMID:25605017 Reduction of miR-29c enhances pancreatic cancer cell migrati... | KEEP AS NON CORE | Summary: Regulation of miRNA transcription (PMID:25605017). Reason: Valid. SMAD3 regulates miRNA transcription. Parent term of both positive and negative regulation annotations. Non-core. |
| 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. |
| 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). |
| GO:0003677 DNA binding | IDA PMID:28467929 PPARΞ³ Links BMP2 and TGFΞ²1 Pathways in Vascular Smooth Muscl... | ACCEPT | Summary: DNA binding confirmed by direct assay (PMID:28467929). Reason: Core molecular function. SMAD3 MH1 domain directly binds DNA. |
| 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. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9731111 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-9731111). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| 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. |
| 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. |
| GO:0005515 protein binding | IPI PMID:23723426 Kindlin-2 mediates activation of TGF-Ξ²/Smad signaling and re... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:23723426). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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. |
| 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. |
| 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: RNA polymerase II cis-regulatory region sequence-specific DNA binding confirmed (PMID:18832382). Reason: Core molecular function. SMAD3 binds SBEs in Pol II-regulated cis-regulatory regions. |
| 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. |
| 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. |
| 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: RNA polymerase II cis-regulatory region sequence-specific DNA binding confirmed (PMID:31582430). Reason: Core molecular function. SMAD3 binds SBEs in Pol II-regulated cis-regulatory regions. |
| 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. |
| 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. |
| 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. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: ISA from TFClass database for DNA-binding TF activity Pol II-specific. Reason: Correct. SMAD3 is classified as a TF in TFClass. Also supported by IDA and IBA. |
| 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 functions as a DNA-binding transcription factor that directly binds SMAD binding elements (SBE: GTCT/AGAC) and CAGA-box motifs through its MH1 domain, and regulates RNA polymerase II-dependent transcription of TGF-beta responsive genes. Reason: Core molecular function. SMAD3 is a bona fide sequence-specific DNA-binding transcription factor. Its MH1 domain directly contacts DNA at SBE sequences, and it recruits transcriptional coactivators (p300/CBP) or corepressors (Ski/SnoN) to regulate Pol II transcription. Consistent with IBA and ISA evidence already accepted for this term. |
| 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. |
| GO:0005515 protein binding | IPI PMID:25556234 New host factors important for respiratory syncytial virus (... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25556234). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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. |
| GO:0017151 DEAD/H-box RNA helicase binding | IPI PMID:18548003 SMAD proteins control DROSHA-mediated microRNA maturation. | ACCEPT | Summary: DEAD/H-box RNA helicase binding. SMAD3 interacts with DDX5 (p68) (PMID:18548003). Reason: Documented interaction. DDX5/p68 modulates SMAD3-dependent transcription. |
| GO:0005515 protein binding | IPI PMID:24613385 Hsp70 and Hsp90 oppositely regulate TGF-Ξ² signaling through ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:24613385). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0031962 nuclear mineralocorticoid receptor binding | IPI PMID:12902338 Identification of glucocorticoid receptor domains involved i... | KEEP AS NON CORE | Summary: Nuclear mineralocorticoid receptor binding. SMAD3 interacts with NR3C2 (PMID:12902338). Reason: Documented interaction representing transcriptional cross-talk between TGF-beta and mineralocorticoid signaling. |
| 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. |
| 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. |
| 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. |
| GO:0051481 negative regulation of cytosolic calcium ion concentration | IDA PMID:27038547 MiRNA-199a-5p influences pulmonary artery hypertension via d... | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytosolic calcium ion concentration (PMID:27038547). Reason: Indirect downstream effect. SMAD3 as a transcription factor does not directly regulate calcium concentrations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6781764 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-6781764). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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: RNA polymerase II cis-regulatory region sequence-specific DNA binding confirmed (PMID:21947082). Reason: Core molecular function. SMAD3 binds SBEs in Pol II-regulated cis-regulatory regions. |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: Regulation of transcription by RNA polymerase II confirmed (PMID:21947082). Reason: Core biological process. SMAD3 regulates Pol II transcription at target genes. |
| 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. |
| GO:0010628 positive regulation of gene expression | IDA PMID:21307346 Response gene to complement 32 interacts with Smad3 to promo... | ACCEPT | Summary: Positive regulation of gene expression (PMID:21307346). Reason: Core biological process. SMAD3 activates expression of TGF-beta target genes. |
| GO:0005515 protein binding | IPI PMID:20129061 TMEPAI, a transmembrane TGF-beta-inducible protein, sequeste... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:20129061). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:24627487 C18 ORF1, a novel negative regulator of transforming growth ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:24627487). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0070412 R-SMAD binding | IPI PMID:20129061 TMEPAI, a transmembrane TGF-beta-inducible protein, sequeste... | ACCEPT | Summary: R-SMAD binding confirmed. SMAD3 binds other R-SMADs (SMAD2) and itself (PMID:20129061). Reason: Well-supported interaction. SMAD3 interacts with SMAD2 as part of the TGF-beta signaling pathway. Supporting Evidence: PMID:9311995 we observed TbetaR-activation-dependent interaction between Smad2 and Smad3 |
| 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. |
| 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. |
| GO:0071144 heteromeric SMAD protein complex | IDA PMID:21828274 HEB and E2A function as SMAD/FOXH1 cofactors. | ACCEPT | Summary: Heteromeric SMAD protein complex confirmed (PMID:21828274). Reason: Core cellular component. SMAD3/SMAD4 heterotrimer is the functional transcriptional complex. |
| 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. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2176475 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2176475). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2176491 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2176491). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2176502 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2176502). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2176503 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2176503). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2179274 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2179274). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-1535903 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-1535903). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-173481 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-173481). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-173488 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-173488). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-173545 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-173545). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-209055 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-209055). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2106579 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2106579). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2127257 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2127257). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2186607 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2186607). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2186643 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2186643). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187309 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2187309). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187325 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2187325). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187330 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2187330). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187388 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2187388). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-870449 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-870449). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-870538 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-870538). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878143 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-8878143). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878178 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-8878178). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8952226 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-8952226). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9617996 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9617996). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9618004 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9618004). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9618021 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9618021). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9733207 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9733207). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9733247 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9733247). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736959 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9736959). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736970 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9736970). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736979 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9736979). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736984 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9736984). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9736992 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9736992). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9737710 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9737710). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9823952 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9823952). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9823959 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-9823959). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-2186736 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-NUL-2186736). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-2186755 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-NUL-2186755). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9625758 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-NUL-9625758). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3315483 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-3315483). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2187395 | ACCEPT | Summary: Nucleoplasm localization (Reactome:R-HSA-2187395). Reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1549526 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-1549526). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170847 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-170847). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170850 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-170850). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170868 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-170868). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-173488 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-173488). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2031355 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2031355). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2106579 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2106579). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187355 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2187355). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187401 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2187401). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187405 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2187405). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3311014 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-3311014). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9008928 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-9008928). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9009910 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-9009910). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| 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. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | ACCEPT | Summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:21947082). Reason: Core molecular function of SMAD3. Directly binds DNA and regulates transcription. |
| GO:0005515 protein binding | IPI PMID:21947082 USP15 is a deubiquitylating enzyme for receptor-activated SM... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21947082). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| GO:0005515 protein binding | IPI PMID:21307346 Response gene to complement 32 interacts with Smad3 to promo... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21307346). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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. |
| GO:0005515 protein binding | IPI PMID:19289081 Nuclear export of Smad2 and Smad3 by RanBP3 facilitates term... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19289081). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:9865696 SARA, a FYVE domain protein that recruits Smad2 to the TGFbe... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:9865696). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:9892009 Roles of pathway-specific and inhibitory Smads in activin re... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:9892009). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0032924 activin receptor signaling pathway | IMP PMID:15150278 Nodal and ALK7 inhibit proliferation and induce apoptosis in... | ACCEPT | Summary: Activin receptor signaling pathway confirmed (PMID:15150278). Reason: Core biological process. SMAD3 mediates activin signaling through ACVR1B. |
| 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. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170835 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-170835). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187358 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2187358). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187368 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2187368). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187375 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2187375). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187382 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2187382). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2187395 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-2187395). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3656523 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-3656523). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9008692 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-9008692). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9727922 | ACCEPT | Summary: Cytosol localization (Reactome:R-HSA-9727922). Reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm. |
| GO:0005515 protein binding | IPI PMID:10681527 Identification and characterization of a PDZ protein that in... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:10681527). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0043130 ubiquitin binding | IDA PMID:18794808 Ligand-dependent ubiquitination of Smad3 is regulated by cas... | ACCEPT | Summary: Ubiquitin binding confirmed (PMID:18794808). SMAD3 is subject to monoubiquitination that regulates DNA binding. Reason: Well-supported by PMID:18794808 and PMID:21947082. Monoubiquitination of SMAD3 prevents DNA binding; USP15 deubiquitination restores it. |
| GO:0005515 protein binding | IPI PMID:17469184 Involvement of the constitutive complex formation of c-Ski/S... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:17469184). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:18832382 HMGA2 and Smads co-regulate SNAIL1 expression during inducti... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:18832382). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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. |
| 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. |
| GO:0005515 protein binding | IPI PMID:15588252 The Smad3 linker region contains a transcriptional activatio... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15588252). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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). |
| GO:0019902 phosphatase binding | IPI PMID:16751101 PPM1A functions as a Smad phosphatase to terminate TGFbeta s... | ACCEPT | Summary: Phosphatase binding. SMAD3 binds PPM1A (PMID:16751101). Reason: Well-documented. PPM1A dephosphorylates SMAD3 C-terminal SSXS motif to terminate TGF-beta signaling (PMID:16751101). |
| 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: Protein binding annotation from high-throughput or targeted interaction study (PMID:18568018). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:11278251 Smurf1 interacts with transforming growth factor-beta type I... | ACCEPT | Summary: Ubiquitin protein ligase binding confirmed. SMAD3 interacts with E3 ligases including SMURF2, NEDD4L, STUB1/CHIP (PMID:11278251). Reason: Well-supported. SMAD3 is a substrate of multiple E3 ubiquitin ligases that regulate its stability and function. |
| GO:0005515 protein binding | IPI PMID:15897867 Oligomerization of Evi-1 regulated by the PR domain contribu... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15897867). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:17099224 Potentiation of Smad-mediated transcriptional activation by ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:17099224). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:15647271 The integral inner nuclear membrane protein MAN1 physically ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15647271). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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. |
| GO:0005515 protein binding | IPI PMID:19049980 SKI and MEL1 cooperate to inhibit transforming growth factor... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19049980). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0019901 protein kinase binding | IPI PMID:12874272 Requirement of the co-repressor homeodomain-interacting prot... | ACCEPT | Summary: Protein kinase binding. SMAD3 binds CDK8/CDK9 (PMID:12874272). Reason: SMAD3 interacts with kinases including CDK8/9 that phosphorylate its linker region. |
| 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. |
| 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. |
| GO:0005515 protein binding | IPI PMID:16200078 Cloning and functional characterization of a new Ski homolog... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:16200078). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0005515 protein binding | IPI PMID:17292623 Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP ... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:17292623). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0070410 co-SMAD binding | IPI PMID:8774881 Receptor-associated Mad homologues synergize as effectors of... | ACCEPT | Summary: co-SMAD binding confirmed. SMAD3 directly binds SMAD4 via MH2 domain to form the transcriptionally active heteromeric complex (PMID:8774881). Reason: Core molecular function. SMAD3-SMAD4 interaction is the central event in TGF-beta signal transduction. Supporting Evidence: PMID:9311995 Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells |
| GO:0070410 co-SMAD binding | IPI PMID:9111321 Heteromeric and homomeric interactions correlate with signal... | ACCEPT | Summary: co-SMAD binding confirmed. SMAD3 directly binds SMAD4 via MH2 domain to form the transcriptionally active heteromeric complex (PMID:9111321). Reason: Core molecular function. SMAD3-SMAD4 interaction is the central event in TGF-beta signal transduction. Supporting Evidence: PMID:9311995 Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells |
| GO:0070410 co-SMAD binding | IPI PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: co-SMAD binding confirmed. SMAD3 directly binds SMAD4 via MH2 domain to form the transcriptionally active heteromeric complex (PMID:9311995). Reason: Core molecular function. SMAD3-SMAD4 interaction is the central event in TGF-beta signal transduction. Supporting Evidence: PMID:9311995 Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells |
| GO:0070410 co-SMAD binding | IPI PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | ACCEPT | Summary: co-SMAD binding confirmed. SMAD3 directly binds SMAD4 via MH2 domain to form the transcriptionally active heteromeric complex (PMID:9732876). Reason: Core molecular function. SMAD3-SMAD4 interaction is the central event in TGF-beta signal transduction. Supporting Evidence: PMID:9311995 Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells |
| GO:0070412 R-SMAD binding | IPI PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: R-SMAD binding confirmed. SMAD3 binds other R-SMADs (SMAD2) and itself (PMID:9311995). Reason: Well-supported interaction. SMAD3 interacts with SMAD2 as part of the TGF-beta signaling pathway. Supporting Evidence: PMID:9311995 we observed TbetaR-activation-dependent interaction between Smad2 and Smad3 |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | ACCEPT | Summary: SMAD3 directly binds to TPA-responsive elements (TREs/AP-1 sites) in promoter cis-regulatory regions. Zhang et al. (1998) showed that Smad3 interacts directly with the TRE and can activate TGF-beta-inducible transcription from the TRE (PMID:9732876). Reason: Core molecular function. SMAD3 directly binds DNA at cis-regulatory regions including SMAD binding elements (SBEs) and TPA-responsive elements (TREs). This is supported by direct assay evidence from Zhang et al. (1998) in Nature. Supporting Evidence: PMID:9732876 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... | ACCEPT | Summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:9732876). Reason: Core molecular function of SMAD3. Directly binds DNA and regulates 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. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9732876 Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-be... | ACCEPT | Summary: SMAD3 activates DNA-templated transcription. Zhang et al. (1998) showed that Smad3 and Smad4 cooperate with c-Jun/c-Fos to activate transcription in response to TGF-beta through TPA-responsive elements (PMID:9732876). Reason: Core biological process. SMAD3 is a transcriptional activator of TGF-beta target genes. Direct assay evidence demonstrates SMAD3 activates transcription both independently and in cooperation with AP-1 factors. 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:0003700 DNA-binding transcription factor activity | IDA PMID:9111321 Heteromeric and homomeric interactions correlate with signal... | ACCEPT | Summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:9111321). Reason: Core molecular function of SMAD3. Directly binds DNA and regulates 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. |
| 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. |
| GO:0031053 primary miRNA processing | TAS PMID:19018011 Holding their own: the noncanonical roles of Smad proteins. | KEEP AS NON CORE | Summary: SMAD3 has been reported to participate in primary miRNA processing through noncanonical roles. Davis et al. showed that SMADs directly interact with DROSHA and facilitate maturation of specific miRNAs (PMID:18548003, PMID:19018011). Reason: Valid but represents a noncanonical function of SMAD3. While SMAD proteins can interact with the DROSHA/DGCR8 microprocessor complex to promote processing of specific pri-miRNAs (e.g., miR-21), this is a secondary function distinct from the core TGF-beta signal transduction and transcriptional regulation roles. |
| 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. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9111321 Heteromeric and homomeric interactions correlate with signal... | ACCEPT | Summary: SMAD3 positively regulates DNA-templated transcription. Shi et al. (1997) demonstrated heteromeric and homomeric interactions of Smad3 and Smad4/DPC4 that correlate with signaling activity and functional cooperativity in transcriptional activation (PMID:9111321). Reason: Core biological process. Positive regulation of transcription is a primary function of SMAD3. This IDA evidence is consistent with other accepted annotations for this GO term. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 a... | ACCEPT | Summary: SMAD3 activates transcription in TGF-beta signaling. Nakao et al. (1997) showed that Smads 2, 3 and 4 showed a synergistic effect in a transcriptional reporter assay using the TGF-beta-inducible PAI-1 promoter (PMID:9311995). Reason: Core biological process. Transcriptional activation is a primary function of SMAD3. Direct assay evidence from Nakao et al. showing synergistic transcriptional activation using a TGF-beta responsive promoter. Supporting Evidence: PMID:9311995 Smads 2, 3 and 4 accumulated in the nucleus upon TGF-beta1 treatment in Mv1Lu cells, and showed a synergistic effect in a transcriptional reporter assay using the TGF-beta-inducible plasminogen activator inhibitor-1 promoter. |
| GO:0005515 protein binding | IPI PMID:19122240 Pin1 down-regulates transforming growth factor-beta (TGF-bet... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19122240). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19122240 Pin1 down-regulates transforming growth factor-beta (TGF-bet... | ACCEPT | Summary: Ubiquitin protein ligase binding confirmed. SMAD3 interacts with E3 ligases including SMURF2, NEDD4L, STUB1/CHIP (PMID:19122240). Reason: Well-supported. SMAD3 is a substrate of multiple E3 ubiquitin ligases that regulate its stability and function. |
| GO:0006955 immune response | IMP PMID:16886151 Association of polymorphisms of IGF1R and genes in the trans... | KEEP AS NON CORE | Summary: SMAD3 participates in immune regulation as a downstream effector of TGF-beta signaling. TGF-beta is a key immunomodulatory cytokine, and SMAD3-dependent signaling regulates T cell differentiation, tolerance, and inflammatory responses (PMID:16886151). Reason: Valid but represents a downstream pleiotropic effect of TGF-beta/SMAD3 signaling rather than a core molecular function. TGF-beta/SMAD3 signaling is critical for immune homeostasis, particularly T regulatory cell differentiation and suppression of inflammatory responses, but this is a pathway-level outcome. |
| GO:0005515 protein binding | IPI PMID:11274402 Inactivation of menin, a Smad3-interacting protein, blocks t... | REMOVE | Summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:11274402). SMAD3 interacts with numerous proteins as a signaling hub. Reason: 'Protein binding' (GO:0005515) is uninformative for a transcription factor and signaling hub like SMAD3. More specific binding terms (co-SMAD binding, R-SMAD binding, TF binding, ubiquitin ligase binding) are preferred and already present in the annotation set. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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... | ACCEPT | Summary: SMAD3 forms homomeric complexes. Zhang et al. (1996) showed that hMAD-3 (SMAD3) associates with itself, and Nakao et al. (1997) demonstrated TGF-beta receptor activation-dependent interaction between SMAD2 and SMAD3, as well as SMAD3 self-association (PMID:8774881, PMID:9311995). Reason: Valid molecular function. SMAD3 forms homotrimers via its MH2 domain, a key step in the signaling pathway. Crystal structures confirm the MH2 domain mediates trimerization. While SMAD3 primarily signals as a heterotrimer with SMAD4, homodimerization/trimerization is a well-documented intrinsic activity. Supporting Evidence: PMID:8774881 hMAD-3 and -4 synergized to induce strong ligand-independent TGF-beta-like responses. |
| 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... | ACCEPT | Summary: SMAD3 directly binds DNA in a sequence-specific manner. The MH1 domain of SMAD3 recognizes the SMAD binding element (SBE: GTCT/AGAC) and CAGA-box variants. Structural studies confirm zinc-dependent DNA binding by the MH1 domain (PMID:10823886, PMID:12686552). Reason: Core molecular function. Sequence-specific DNA binding through the MH1 domain is a fundamental activity of SMAD3. This is well-established by crystal structures, EMSA, and ChIP experiments. Consistent with the IEA annotation for this term already accepted. |
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