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.
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GO:0005634
nucleus
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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.
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GO:0005737
cytoplasm
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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.
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GO:0030308
negative regulation of cell growth
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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.
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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.
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GO:0043235
receptor complex
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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.
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GO:0043565
sequence-specific DNA binding
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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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organism: human
gene_id: SMAD3
gene_symbol: SMAD3
uniprot_accession: P84022
protein_description: 'RecName: Full=SMAD family member 3 {ECO:0000312|HGNC:HGNC:6769};
Short=SMAD 3 {ECO:0000305}; Short=hSMAD3; AltName: Full=JV15-2; AltName: Full=Mothers
against decapentaplegic homolog 3; Short=MAD homolog 3; Short=Mad3; Short=Mothers
against DPP homolog 3; Short=hMAD-3;'
gene_info: Name=SMAD3 {ECO:0000312|HGNC:HGNC:6769}; Synonyms=MADH3;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the dwarfin/SMAD family. .
protein_domains: Dwarfin. (IPR013790); MAD_homology1_Dwarfin-type. (IPR003619);
MAD_homology_MH1. (IPR013019); SMAD-like_dom_sf. (IPR017855); SMAD_dom_Dwarfin-type.
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BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SMAD3' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene SMAD3 (gene ID: SMAD3, UniProt: P84022) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SMAD3' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene SMAD3 (gene ID: SMAD3, UniProt: P84022) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Title: Functional annotation of human SMAD3 (UniProt P84022)
Plan and verification. We verified the target as human SMAD3, a receptor-regulated SMAD (RβSMAD) in the dwarfin/SMAD family. SMAD3 comprises an Nβterminal MH1 DNAβbinding domain, a Cβterminal MH2 proteinβinteraction domain, and a regulatory linker; this architecture underlies its role as a transcriptional effector of TGFβΞ²/Activin signaling (wang2023smadproteinsin pages 1-2, danielpour2024advancesandchallenges pages 12-13). Below we synthesize current evidence with emphasis on 2023β2025 sources and translational applications.
Key concepts and definitions. SMAD3 is the principal RβSMAD that, upon activation by TGFβΞ² type I receptor (TGFBR1/ALK5), forms oligomers with the coβSMAD, SMAD4, to regulate target genes. The MH1 domain binds short Smadβbinding elements (SBE, 5β²βGTCT/AGACβ3β²) and CAGAβbox variants, whereas MH2 mediates receptor docking, SMAD4 assembly, and cofactor recruitment; the linker integrates regulatory postβtranslational modifications (PTMs) (wang2023smadproteinsin pages 1-2, danielpour2024advancesandchallenges pages 12-13). Because Smad core motifs are only 4 bp, SMAD3 complexes have intrinsically low DNA affinity and rely on cooperating transcription factors (e.g., APβ1) and composite motifs to achieve specificity (itoh2024analysisofthe pages 1-2).
Recent mechanistic developments (2023β2025 priority). New analyses emphasize DNA recognition and context dependence. CASTing of endogenous Smad2/3βSmad4 complexes across cell types showed differential preference for SBE vs CAGA and frequent enrichment of Fos/Jun motifs; composite elements were required for robust TGFβΞ² responses, explaining cellβtype dependence (The FASEB Journal, 2024; https://doi.org/10.1096/fj.202400978r) (itoh2024analysisofthe pages 1-2). Reviews in 2024 synthesized PTM logic: ALK5 phosphorylates the SMAD3 Cβterminal SSXS motif to enable trimerization with SMAD4 and nuclear import; linker phosphorylation by ERK/MAPK and CDK8/9 tunes transcriptional output and cofactor engagement, while PPM1A dephosphorylation and RanBP3 export terminate signaling (Pharmaceuticals, 2024; https://doi.org/10.3390/ph17040533; Pharmaceuticals, 2024; https://doi.org/10.3390/ph17030326) (danielpour2024advancesandchallenges pages 12-13, runa2024targetingsmaddependentsignaling pages 2-4, runa2024targetingsmaddependentsignaling pages 8-9). Singleβcell work highlighted distinct SMAD3 dynamics, including often higher basal nuclear localization than SMAD2 and nonβredundant ligand responses, reinforcing differential roles within the Smad2/3 pair (2024; https://doi.org/10.26083/tuprints-00028725) (huang2024investigatingsmadsignaling pages 81-84).
Biochemical role and pathway placement. In canonical TGFβΞ² signaling, ligandβbound TGFBR2 phosphorylates ALK5, which then phosphorylates SMAD3 at the Cβterminal SSXS motif; phosphoβSMAD3 dissociates, oligomerizes primarily as a heterotrimer with SMAD4, and translocates to the nucleus to regulate transcription with coactivators (e.g., p300/CBP) or corepressors (e.g., TGIF, Ski/Sno) (Pharmaceuticals, 2024; https://doi.org/10.3390/ph17040533) (danielpour2024advancesandchallenges pages 12-13). SMAD3βs linker is a regulatory hub targeted by ERK/MAPK, CDKs and other kinases; phosphatases (PPM1A, SCPs) and E3 ligases (SMURF/NEDD4L) modulate turnover and signal duration (Pharmaceuticals, 2024; https://doi.org/10.3390/ph17030326) (runa2024targetingsmaddependentsignaling pages 8-9). Functionally, SMAD3 contributes to EMT programs and extracellular matrix gene induction; differential DNAβbinding capacity versus SMAD2 (SMAD2βs MH1 insertion restricts direct DNA binding) gives SMAD3 a prominent direct chromatinβengagement role (danielpour2024advancesandchallenges pages 12-13).
Subcellular localization and dynamics. SMAD3 shuttles constitutively between cytoplasm and nucleus; receptorβmediated phosphorylation exposes/imports MH1βencoded NLSs via importinβΞ² pathways. Export is driven by RanBP3 and exportins when SMAD3 is dephosphorylated by PPM1A; SMAD4 import relies on importinβΞ± and nuclear pore components participate in flux (Pharmaceuticals, 2024; https://doi.org/10.3390/ph17030326) (runa2024targetingsmaddependentsignaling pages 2-4). Singleβcell studies report that SMAD3 can be constitutively more nuclear than SMAD2 and that its interaction with SMAD4 differs dynamically even when SSXS sites are phosphorylated, contributing to distinct signaling kinetics (2024; https://doi.org/10.26083/tuprints-00028725) (huang2024investigatingsmadsignaling pages 81-84).
Genome binding and enhancer logic. Genomeβwide and CASTing studies show that Smad complexes bind short SBEs/CAGA motifs with low affinity and typically require adjacent TF motifs (e.g., APβ1) at enhancers to stabilize occupancy and drive transcription, explaining strong context dependence. Reporter assays validated that composite elements potentiate cell typeβspecific TGFβΞ² responses (FASEB J, 2024; https://doi.org/10.1096/fj.202400978r) (itoh2024analysisofthe pages 1-2). Methodologically, a multiplexed TRβFRET uHTS assay now enables simultaneous monitoring of SMAD4βSMAD3 PPI and SBE DNA binding at singleβaminoβacid resolution, and has identified initial smallβmolecule hits that disrupt the SMAD4βSMAD3βDNA complex (J Mol Cell Biol, 2023; https://doi.org/10.1093/jmcb/mjad068) (ouyang2023amultiplexedtimeresolved pages 1-2).
Cellular location of function. SMAD3 functions in both cytoplasm (activation and complex assembly) and nucleus (transcriptional regulation). Its transcriptional activity depends on nuclear accumulation with SMAD4 and on engagement of coactivators/corepressors; termination involves nuclear export following dephosphorylation (runa2024targetingsmaddependentsignaling pages 2-4, danielpour2024advancesandchallenges pages 12-13).
Disease relevance and phenotypes. SMAD3 is integral to fibrotic programs and cancer biology via TGFβΞ²βdriven EMT and matrix deposition; perturbations in TGFβΞ²/SMAD signaling can support tumor progression and immune evasion, while intact signaling provides tumorβsuppressive effects in early diseaseβunderscoring contextβdependent roles (Diagnostics, 2023; https://doi.org/10.3390/diagnostics13172769) (wang2023smadproteinsin pages 17-19). Inherited defects within the TGFβΞ²βSMAD axis cause syndromic aortopathy; SMAD3 is the defining gene for LoeysβDietz syndrome type 3, and its downstream signaling contributes to vascular remodeling and aneurysm risk across the TGFβΞ² pathway disorders (wang2023smadproteinsin pages 17-19). Expert immunoβoncology perspectives further highlight TGFβΞ²βs control of antiβtumor immunity, with SMAD2/3 as key intracellular mediators (Nature Reviews Immunology, 2023; https://doi.org/10.1038/s41577-022-00796-z) (wang2023smadproteinsin pages 17-19).
Therapeutics and realβworld implementations. Upstream TGFβΞ² pathway inhibitors include ALK5 smallβmolecule inhibitors (e.g., galunisertib/LY2157299; vactosertib/TEWβ7197) and panβTGFβΞ² neutralizing antibodies/ligand traps (e.g., fresolimumab). Reviews in 2024β2025 outline their clinical exploration in oncology and fibrosis and emphasize challenges from pathway pleiotropy (Pharmaceuticals, 2024; https://doi.org/10.3390/ph17040533) (danielpour2024advancesandchallenges pages 12-13). Novel combinatorial strategies include a dual ALK5/VEGFR2 inhibitor (TU2218) that enhances immuneβmediated antitumor effects and synergizes with checkpoint blockade in preclinical models, illustrating rational coβtargeting of TGFβΞ²/VEGF axes (Cancer Immunol Immunother, 2024; https://doi.org/10.1007/s00262-024-03777-4) (danielpour2024advancesandchallenges pages 12-13). Downstream targeting is emerging: a uHTS TRβFRET platform directly screens for inhibitors of the SMAD4βSMAD3βDNA complex, identifying initial hit chemotypes and providing a route to modulate nuclear SMAD function selectively (J Mol Cell Biol, 2023; https://doi.org/10.1093/jmcb/mjad068) (ouyang2023amultiplexedtimeresolved pages 1-2). Expert reviews recommend cellβtypeβ and contextβguided strategies and, where possible, selective interference at SMAD nodes to mitigate systemic toxicity (wang2023smadproteinsin pages 17-19, danielpour2024advancesandchallenges pages 12-13).
Relevant statistics and data highlights. Quantitative DNAβbinding studies show Smad complexesβ low intrinsic affinity for 4βbp SBE cores (Kd on the order of ~10^β7 M), necessitating cooperative binding at composite motifs; CASTing revealed motifβusage shifts among A549, HepG2, and HaCaT cells, aligning with changes in Smad complex composition and partner TF availability (FASEB J, 2024; https://doi.org/10.1096/fj.202400978r) (itoh2024analysisofthe pages 1-2). Screening statistics from an FDAβapproved bioactive library using the uHTS TRβFRET assay yielded tractable hits (gambogic/gambogenic acids), validating feasibility of highβthroughput disruption of SMAD4βSMAD3βDNA assemblies (J Mol Cell Biol, 2023; https://doi.org/10.1093/jmcb/mjad068) (ouyang2023amultiplexedtimeresolved pages 1-2).
Expert analyses and opinions. Contemporary reviews argue that because systemic TGFβΞ² blockade can impair tissue homeostasis, precise targeting of SMADβdependent mechanismsβguided by singleβcell context, enhancer grammar, and PTM stateβmay produce better therapeutic indices in cancer and fibrosis (Pharmaceuticals, 2024; https://doi.org/10.3390/ph17040533; Diagnostics, 2023; https://doi.org/10.3390/diagnostics13172769) (wang2023smadproteinsin pages 17-19, danielpour2024advancesandchallenges pages 12-13). Immunoβoncology perspectives underscore integrating TGFβΞ²/SMAD inhibition with immune checkpoint therapies to reverse exclusion and stromal barriers (Nature Reviews Immunology, 2023; https://doi.org/10.1038/s41577-022-00796-z) (wang2023smadproteinsin pages 17-19).
Primary function and cellular site of action summarized. SMAD3 is a sequenceβspecific transcription factor and signal transducer. It is not an enzyme or transporter; rather, it is phosphorylated at its Cβterminal SSXS motif by ALK5, complexes with SMAD4, and regulates gene expression by binding SBE/CAGAβcontaining enhancers and promoters with cofactors. Its functional activity occurs in the nucleus following cytoplasmic activation and translocation (runa2024targetingsmaddependentsignaling pages 2-4, danielpour2024advancesandchallenges pages 12-13, itoh2024analysisofthe pages 1-2).
| Aspect | Key facts | Primary sources (authors, year; journal) | URL/DOI |
|---|---|---|---|
| Identity & domains | - Receptor-regulated SMAD (R-SMAD) belonging to the dwarfin/SMAD family - Conserved MH1 (N-term, DNA-binding) and MH2 (C-term, protein interaction) domains; regulatory linker between them |
Wang Q. et al., 2023; Diagnostics; Danielpour D., 2024; Pharmaceuticals (wang2023smadproteinsin pages 1-2, danielpour2024advancesandchallenges pages 12-13) | doi:10.3390/diagnostics13172769; https://doi.org/10.3390/ph17040533 |
| Canonical activation | - TGF-Ξ²RI/ALK5 phosphorylates the C-terminal SSXS motif on SMAD3 - Phosphorylated SMAD3 oligomerizes with SMAD4 and translocates to nucleus; recruitment aided by adaptors (e.g., SARA) |
Runa F. et al., 2024; Pharmaceuticals; Danielpour D., 2024; Pharmaceuticals (runa2024targetingsmaddependentsignaling pages 2-4, danielpour2024advancesandchallenges pages 12-13) | 10.3390/ph17030326; https://doi.org/10.3390/ph17040533 |
| DNA recognition | - SMAD3/SMAD4 complexes bind SBE (GTCT/AGAC) and CAGA motifs but have low intrinsic DNA affinity - Require cooperating TFs (e.g., AP-1) and composite motifs for stable, cell-type-specific binding |
Itoh Y. et al., 2024; The FASEB Journal; Ouyang W. et al., 2023; J Mol Cell Biol (itoh2024analysisofthe pages 1-2, ouyang2023amultiplexedtimeresolved pages 1-2) | https://doi.org/10.1096/fj.202400978r; https://doi.org/10.1093/jmcb/mjad068 |
| Nuclear shuttling | - Dynamic cytoplasmβnucleus shuttling mediated by importins/exportins (importin-Ξ²/Ξ±, RanBP3) and nuclear pores - Termination/export promoted by phosphatase PPM1A (dephosphorylates C-term) |
Runa F. et al., 2024; Pharmaceuticals; Huang Z., 2024 (runa2024targetingsmaddependentsignaling pages 2-4, huang2024investigatingsmadsignaling pages 81-84) | 10.3390/ph17030326; https://doi.org/10.26083/tuprints-00028725 |
| Post-translational regulation | - Linker phosphorylation by ERK/MAPK and CDK8/9 modulates transcriptional output - Ubiquitin ligases (SMURF family, NEDD4L, etc.) drive proteasomal turnover; phosphatases (PPM1A, SCPs) reverse phosphorylation |
Runa F. et al., 2024; Pharmaceuticals; Danielpour D., 2024; Pharmaceuticals (runa2024targetingsmaddependentsignaling pages 8-9, danielpour2024advancesandchallenges pages 12-13) | 10.3390/ph17030326; https://doi.org/10.3390/ph17040533 |
| Enhancer logic & context dependence | - SMAD complexes often act at distal enhancers and require nearby TF motifs (APβ1, FOXO1 etc.) to drive context-specific transcription - Genome-wide assays (CASTing/ChIP) reveal cell-type motif preferences and composite-site dependence |
Itoh Y. et al., 2024; The FASEB Journal; Ouyang W. et al., 2023; J Mol Cell Biol (itoh2024analysisofthe pages 1-2, ouyang2023amultiplexedtimeresolved pages 1-2) | https://doi.org/10.1096/fj.202400978r; https://doi.org/10.1093/jmcb/mjad068 |
| Disease genetics | - Pathogenic SMAD3/TGFβΞ² axis variants underlie vascular/connective-tissue phenotypes (LoeysβDietzβrelated aortopathy) and contribute to fibrotic and cancer biology - Dysregulated SMAD3 signaling implicated in fibrosis, tumor progression, and immune modulation |
Wang Q. et al., 2023; Diagnostics; Danielpour D., 2024; Pharmaceuticals (wang2023smadproteinsin pages 17-19, danielpour2024advancesandchallenges pages 12-13) | doi:10.3390/diagnostics13172769; https://doi.org/10.1186/s12967-024-05411-4 |
| Therapeutic applications | - Upstream inhibitors: ALK5 inhibitors (galunisertib, vactosertib) and panβTGFβΞ² traps (fresolimumab) in clinical/preclinical exploration - Dual-target strategies (e.g., ALK5/VEGFR TU2218) and direct SMAD4βSMAD3βDNA screening (TRβFRET uHTS) enable downstream/combination approaches |
Danielpour D., 2024; Pharmaceuticals; Kim N.-H. et al., 2024; Cancer Immunol Immunother; Ouyang W. et al., 2023; J Mol Cell Biol (danielpour2024advancesandchallenges pages 12-13, ouyang2023amultiplexedtimeresolved pages 1-2) | https://doi.org/10.3390/ph17040533; https://doi.org/10.1007/s00262-024-03777-4; https://doi.org/10.1093/jmcb/mjad068 |
Table: Compact reference table summarizing SMAD3 identity, mechanism, regulation, genomic binding logic, disease links, and therapeutic strategies with primary 2023β2025 sources (pqac context IDs). This provides a quick evidenceβlinked overview for functional annotation and research planning.
Citations with URLs and dates
- Wang Q. et al., 2023, Diagnostics 13:2769. SMAD proteins in TGFβΞ² signalling pathway in cancer. https://doi.org/10.3390/diagnostics13172769 (Accessed 2026) (wang2023smadproteinsin pages 1-2, wang2023smadproteinsin pages 17-19).
- Danielpour D., 2024, Pharmaceuticals. Advances and challenges in targeting TGFβΞ² isoforms. https://doi.org/10.3390/ph17040533 (Accessed 2026) (danielpour2024advancesandchallenges pages 12-13).
- Runa F. et al., 2024, Pharmaceuticals. Targeting SMADβdependent signaling. https://doi.org/10.3390/ph17030326 (Accessed 2026) (runa2024targetingsmaddependentsignaling pages 2-4, runa2024targetingsmaddependentsignaling pages 8-9).
- Itoh Y. et al., 2024, The FASEB Journal. DNAβbinding properties of TGFβΞ²βactivated Smad complexes. https://doi.org/10.1096/fj.202400978r (Accessed 2026) (itoh2024analysisofthe pages 1-2).
- Ouyang W. et al., 2023, Journal of Molecular Cell Biology. TRβFRET uHTS assay targeting SMAD4βSMAD3βDNA. https://doi.org/10.1093/jmcb/mjad068 (Accessed 2026) (ouyang2023amultiplexedtimeresolved pages 1-2).
- Huang Z., 2024. Investigating SMAD signaling dynamics and function in single cells. https://doi.org/10.26083/tuprints-00028725 (Accessed 2026) (huang2024investigatingsmadsignaling pages 81-84).
- Nixon B.G. et al., 2023, Nature Reviews Immunology. TGFΞ² control of immune responses in cancer. https://doi.org/10.1038/s41577-022-00796-z (Accessed 2026) (wang2023smadproteinsin pages 17-19).
Limitations. While core mechanistic features are well supported, quantitative PTM kinetics and complete maps of human disease variants specific to SMAD3 were not exhaustively retrieved here; future updates should integrate curated variant databases and clinical genetics cohorts specifically for SMAD3.
References
(wang2023smadproteinsin pages 1-2): Qi Wang, Fei Xiong, Guanhua Wu, Da Wang, Wenzheng Liu, Junsheng Chen, Yongqiang Qi, Bing Wang, and Yongjun Chen. Smad proteins in tgf-Ξ² signalling pathway in cancer: regulatory mechanisms and clinical applications. Diagnostics, 13:2769, Aug 2023. URL: https://doi.org/10.3390/diagnostics13172769, doi:10.3390/diagnostics13172769. This article has 64 citations and is from a poor quality or predatory journal.
(danielpour2024advancesandchallenges pages 12-13): David Danielpour. Advances and challenges in targeting tgf-Ξ² isoforms for therapeutic intervention of cancer: a mechanism-based perspective. Pharmaceuticals, Apr 2024. URL: https://doi.org/10.3390/ph17040533, doi:10.3390/ph17040533. This article has 52 citations and is from a poor quality or predatory journal.
(itoh2024analysisofthe pages 1-2): Yuka Itoh, Kunio Miyake, Daizo Koinuma, Chiho Omata, Masao Saitoh, and Keiji Miyazawa. Analysis of the dnaβbinding properties of tgfβΞ²βactivated smad complexes unveils a possible molecular basis for cellular contextβdependent signaling. The FASEB Journal, Aug 2024. URL: https://doi.org/10.1096/fj.202400978r, doi:10.1096/fj.202400978r. This article has 2 citations.
(runa2024targetingsmaddependentsignaling pages 2-4): Farhana Runa, Gabriela Ortiz-Soto, Natan Roberto de Barros, and Jonathan A. Kelber. Targeting smad-dependent signaling: considerations in epithelial and mesenchymal solid tumors. Pharmaceuticals, 17:326, Mar 2024. URL: https://doi.org/10.3390/ph17030326, doi:10.3390/ph17030326. This article has 17 citations and is from a poor quality or predatory journal.
(runa2024targetingsmaddependentsignaling pages 8-9): Farhana Runa, Gabriela Ortiz-Soto, Natan Roberto de Barros, and Jonathan A. Kelber. Targeting smad-dependent signaling: considerations in epithelial and mesenchymal solid tumors. Pharmaceuticals, 17:326, Mar 2024. URL: https://doi.org/10.3390/ph17030326, doi:10.3390/ph17030326. This article has 17 citations and is from a poor quality or predatory journal.
(huang2024investigatingsmadsignaling pages 81-84): Zixin Huang. Investigating smad signaling dynamics and function in single cells. Text, Jan 2024. URL: https://doi.org/10.26083/tuprints-00028725, doi:10.26083/tuprints-00028725. This article has 0 citations and is from a peer-reviewed journal.
(ouyang2023amultiplexedtimeresolved pages 1-2): Wukun Ouyang, Qianjin Li, Qiankun Niu, Min Qui, Haian Fu, Yuhong Du, and Xiulei Mo. A multiplexed time-resolved fluorescence resonance energy transfer ultrahigh-throughput screening assay for targeting the smad4βsmad3βdna complex. Journal of Molecular Cell Biology, Nov 2023. URL: https://doi.org/10.1093/jmcb/mjad068, doi:10.1093/jmcb/mjad068. This article has 11 citations and is from a peer-reviewed journal.
(wang2023smadproteinsin pages 17-19): Qi Wang, Fei Xiong, Guanhua Wu, Da Wang, Wenzheng Liu, Junsheng Chen, Yongqiang Qi, Bing Wang, and Yongjun Chen. Smad proteins in tgf-Ξ² signalling pathway in cancer: regulatory mechanisms and clinical applications. Diagnostics, 13:2769, Aug 2023. URL: https://doi.org/10.3390/diagnostics13172769, doi:10.3390/diagnostics13172769. This article has 64 citations and is from a poor quality or predatory journal.
id: P84022
gene_symbol: SMAD3
product_type: PROTEIN
status: IN_PROGRESS
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: '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.'
alternative_products:
- name: '1'
id: P84022-1
- name: '2'
id: P84022-2
sequence_note: VSP_042900
- name: '3'
id: P84022-3
sequence_note: VSP_043793
- name: '4'
id: P84022-4
sequence_note: VSP_045348
existing_annotations:
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:9311995
supporting_text: Smad2 and Smad3 interacted with the kinase-deficient TGF-beta type I receptor (TbetaR)-I after it was
phosphorylated by TbetaR-II kinase.
- reference_id: PMID:9732876
supporting_text: Smad3 interacts directly with the TRE and that Smad3 and Smad4 can activate TGF-beta-inducible transcription
from the TRE
- term:
id: GO:0009653
label: anatomical structure morphogenesis
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: SMAD3 is involved in anatomical structure morphogenesis via TGF-beta signaling. IBA supported across species.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0030154
label: cell differentiation
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: SMAD3 is involved in cell differentiation through TGF-beta signaling. IBA supported.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0032924
label: activin receptor signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: SMAD3 also mediates activin receptor signaling, being phosphorylated by ACVR1B. IBA well-supported.
action: ACCEPT
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).
supported_by:
- reference_id: PMID:9892009
supporting_text: Roles of pathway-specific and inhibitory Smads in activin receptor signaling
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:9732876
supporting_text: Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription
- reference_id: PMID:21947082
supporting_text: USP15 is required for TGFbeta and BMP responses in mammalian cells
- term:
id: GO:0060395
label: SMAD protein signal transduction
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: ACCEPT
reason: Core biological process. SMAD3 is one of the principal R-SMADs mediating TGF-beta/activin signal transduction
through the canonical SMAD pathway.
supported_by:
- reference_id: PMID:9311995
supporting_text: 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
- reference_id: PMID:8774881
supporting_text: hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: SMAD3 is a key intracellular mediator of TGF-beta receptor signaling. Activated by TGFBR1/ALK5 phosphorylation.
IBA well-supported.
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated directly by the TGF-beta type I receptor and is essential for
canonical TGF-beta signal transduction.
supported_by:
- reference_id: PMID:8774881
supporting_text: 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
- reference_id: PMID:9311995
supporting_text: Smad2 and Smad3 interacted with the kinase-deficient TGF-beta type I receptor
- term:
id: GO:0071144
label: heteromeric SMAD protein complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: SMAD3 forms heteromeric SMAD complexes with SMAD4 upon TGF-beta stimulation. IBA well-supported across species.
action: ACCEPT
reason: Core cellular component. The SMAD3/SMAD4 heteromeric complex is the functional unit of TGF-beta signaling. Crystal
structure solved (PMID:15350224).
supported_by:
- reference_id: PMID:9311995
supporting_text: TGF-beta induces heteromeric complexes of Smads 2, 3 and 4
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: SMAD3 positively regulates transcription by RNA polymerase II at TGF-beta target gene promoters. IBA supported.
action: ACCEPT
reason: Core biological process. SMAD3/SMAD4 complexes recruit p300/CBP coactivators to activate transcription of TGF-beta
responsive genes.
supported_by:
- reference_id: PMID:9732876
supporting_text: Smad3 and Smad4 also act together with c-Jun and c-Fos to activate transcription in response to TGF-beta
- term:
id: GO:0070411
label: I-SMAD binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: SMAD3 binds inhibitory SMADs (SMAD6/SMAD7). IBA supported across the SMAD family.
action: ACCEPT
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.
- term:
id: GO:0003677
label: DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IEA for DNA binding. SMAD3 directly binds DNA through MH1 domain at SBE sequences.
action: ACCEPT
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.
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IEA for nucleus localization. SMAD3 translocates to nucleus upon TGF-beta stimulation.
action: ACCEPT
reason: Well-supported. SMAD3 is found in nucleus upon activation. Multiple IDA annotations also confirm this.
- term:
id: GO:0005667
label: transcription regulator complex
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IEA for transcription regulator complex. SMAD3 forms complexes with SMAD4 and other transcription factors.
action: ACCEPT
reason: Correct. SMAD3/SMAD4 complexes function as transcription regulator complexes. Also supported by IDA (PMID:21947082).
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IEA for cytoplasm localization. SMAD3 resides in cytoplasm when inactive.
action: ACCEPT
reason: Well-supported. SMAD3 shuttles between cytoplasm and nucleus, residing primarily in cytoplasm before TGF-beta
stimulation.
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IEA for regulation of DNA-templated transcription based on InterPro domain mapping.
action: ACCEPT
reason: Correct. SMAD3 is a transcription factor that regulates DNA-templated transcription. Consistent with experimental
annotations.
- term:
id: GO:0032502
label: developmental process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: IEA for developmental process. Very broad term from ARBA prediction.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0046872
label: metal ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IEA for metal ion binding from UniProt keyword mapping. SMAD3 MH1 domain coordinates a zinc ion essential for
DNA binding.
action: MODIFY
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_replacement_terms:
- id: GO:0008270
label: zinc ion binding
- term:
id: GO:0071363
label: cellular response to growth factor stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: IEA for cellular response to growth factor stimulus. SMAD3 mediates TGF-beta responses.
action: ACCEPT
reason: Correct but broad. SMAD3 mediates cellular responses to TGF-beta and activin, which are growth factors. More specific
pathway terms are also annotated.
- term:
id: GO:0141091
label: transforming growth factor beta receptor superfamily signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: IEA for TGF-beta receptor superfamily signaling pathway from ARBA.
action: ACCEPT
reason: Correct. SMAD3 is a core mediator of TGF-beta receptor superfamily signaling. More specific TGF-beta pathway terms
are also present.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11278756
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:11278756). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11387212
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:11387212). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12154125
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:12154125). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12650946
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:12650946). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12857746
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:12857746). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:14525983
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:14525983). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15084259
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15084259). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15231748
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15231748). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15350224
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15350224). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15527767
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15527767). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16007207
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:16007207). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17785517
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:17785517). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18548003
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:18548003). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18729074
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:18729074). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19032343
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19032343). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19135894
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19135894). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20061380
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:20061380). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20211142
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:20211142). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21258410
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21258410). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21297662
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21297662). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21532621
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21532621). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21597466
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21597466). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21828274
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21828274). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21988832
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21988832). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22045334
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:22045334). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22442258
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:22442258). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22538441
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:22538441). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25416956). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25502805
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25502805). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25609649
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25609649). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25670079
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25670079). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25910212
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25910212). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26680585
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:26680585). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:27107012
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:27107012). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28471448
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:28471448). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29892012
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:29892012). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29997244
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:29997244). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31515488
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:31515488). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:32296183). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:32814053). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:33961781). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35512704
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:35512704). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:39243984
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:39243984). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:18729074
review:
summary: SMAD3 forms homo-oligomers. Confirmed by co-immunoprecipitation and structural studies.
action: ACCEPT
reason: SMAD3 homo-oligomerization is well-documented. Crystal structure shows SMAD3 trimeric assembly (PMID:11224571).
supported_by:
- reference_id: PMID:9732876
supporting_text: Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:22045334
review:
summary: SMAD3 forms homo-oligomers. Confirmed by co-immunoprecipitation and structural studies.
action: ACCEPT
reason: SMAD3 homo-oligomerization is well-documented. Crystal structure shows SMAD3 trimeric assembly (PMID:11224571).
supported_by:
- reference_id: PMID:9732876
supporting_text: Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of Pol II transcription. SMAD3 can also repress transcription
at certain loci.
action: ACCEPT
reason: SMAD3 acts as both transcriptional activator and repressor depending on context and cofactors (Ski/SnoN, TGIF).
Also supported by IDA (PMID:28467929).
- term:
id: GO:0000165
label: MAPK cascade
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for MAPK cascade.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0000977
label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IEA (Ensembl/UniProt) for RNA polymerase II transcription regulatory region sequence-specific DNA binding.
action: ACCEPT
reason: Correct. SMAD3 binds SBE sequences in Pol II regulatory regions. Also supported by IDA annotations.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for DNA-binding transcription activator activity, Pol II-specific.
action: ACCEPT
reason: Correct. SMAD3 activates Pol II transcription at TGF-beta target genes. Also supported by multiple IDA annotations.
- term:
id: GO:0001649
label: osteoblast differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for osteoblast differentiation from mouse data.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. SMAD3 regulates osteoblast differentiation and chondrogenesis (UniProt confirms SMAD3
is a regulator of osteogenesis). Non-core pleiotropic process.
- term:
id: GO:0001657
label: ureteric bud development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for ureteric bud development from mouse data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0001836
label: release of cytochrome c from mitochondria
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for release of cytochrome c from mitochondria from rat data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0003682
label: chromatin binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for chromatin binding from mouse data.
action: ACCEPT
reason: Correct. SMAD3 binds chromatin at enhancer/promoter regions. Also supported by IDA chromatin localization (PMID:21828274).
- term:
id: GO:0003690
label: double-stranded DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for double-stranded DNA binding from mouse data.
action: ACCEPT
reason: Correct. Crystal structure confirms SMAD3 MH1 domain binds dsDNA at SBE sequences (PMID:9741623, PMID:12686552).
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IEA for DNA-binding transcription factor activity.
action: ACCEPT
reason: Correct. SMAD3 is a bona fide DNA-binding transcription factor. Also supported by multiple IDA annotations.
- term:
id: GO:0005518
label: collagen binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for collagen binding from mouse data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for plasma membrane localization from mouse data.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for TGF-beta receptor signaling pathway from rat orthologs.
action: ACCEPT
reason: Correct. Core biological process for SMAD3. Also supported by multiple IDA and IMP annotations.
- term:
id: GO:0007254
label: JNK cascade
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for JNK cascade from mouse data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0008013
label: beta-catenin binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
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.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0008285
label: negative regulation of cell population proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of cell population proliferation from rat data.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0010332
label: response to gamma radiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for response to gamma radiation from rat data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0010467
label: gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for gene expression from mouse data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0019899
label: enzyme binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for enzyme binding from rat data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0023019
label: signal transduction involved in regulation of gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for signal transduction involved in regulation of gene expression from rat data.
action: ACCEPT
reason: 'Correct description of SMAD3 core function: signal transduction (TGF-beta pathway) that directly regulates gene
expression.'
- term:
id: GO:0030325
label: adrenal gland development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for adrenal gland development from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Very specific developmental process likely reflecting broad TGF-beta pathway pleiotropic effects. No direct evidence
for SMAD3-specific role in human adrenal development.
- term:
id: GO:0030335
label: positive regulation of cell migration
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of cell migration from rat data.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0030501
label: positive regulation of bone mineralization
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of bone mineralization from rat data.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. UniProt notes SMAD3 is a regulator of osteogenesis. Non-core tissue-specific process.
- term:
id: GO:0031490
label: chromatin DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for chromatin DNA binding from mouse data.
action: ACCEPT
reason: Correct. SMAD3 binds DNA within chromatin context at enhancers and promoters. Supported by ChIP studies.
- term:
id: GO:0032332
label: positive regulation of chondrocyte differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of chondrocyte differentiation from mouse data.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. UniProt notes SMAD3 is a regulator of chondrogenesis. Non-core developmental process.
- term:
id: GO:0032731
label: positive regulation of interleukin-1 beta production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of IL-1 beta production from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect downstream effect of TGF-beta signaling in immune regulation. Not a direct function of SMAD3 as a transcription
factor.
- term:
id: GO:0032916
label: positive regulation of transforming growth factor beta3 production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of TGF-beta3 production from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: While SMAD3 could transcriptionally regulate TGF-beta3 expression as a feedback mechanism, this is a very specific
downstream effect. Limited direct human evidence.
- term:
id: GO:0032993
label: protein-DNA complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for protein-DNA complex from mouse data.
action: ACCEPT
reason: Correct. SMAD3 forms protein-DNA complexes at SBE-containing regulatory regions. Crystal structure of SMAD3 MH1-DNA
complex solved (PMID:12686552).
- term:
id: GO:0033689
label: negative regulation of osteoblast proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of osteoblast proliferation from mouse data.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect consistent with SMAD3 role in osteogenesis regulation. Non-core tissue-specific process.
- term:
id: GO:0036120
label: cellular response to platelet-derived growth factor stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for cellular response to PDGF stimulus from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect. PDGF may modulate TGF-beta/SMAD signaling through MAPK crosstalk, but SMAD3 is not a direct mediator
of PDGF responses.
- term:
id: GO:0042110
label: T cell activation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for T cell activation from mouse data.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0042177
label: negative regulation of protein catabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of protein catabolic process from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect downstream effect. While TGF-beta signaling can affect protein stability, this is not a direct SMAD3
function.
- term:
id: GO:0042220
label: response to cocaine
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for response to cocaine from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Highly specific environmental response likely from rat neurological studies. No evidence SMAD3 directly mediates
cocaine responses. Over-annotation from ortholog transfer.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for identical protein binding from mouse data.
action: ACCEPT
reason: Correct. SMAD3 forms homomeric complexes. SMAD3 homo-oligomerization is well-documented (PMID:9670020).
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of apoptotic process from rat data.
action: KEEP_AS_NON_CORE
reason: Context-dependent downstream effect. TGF-beta/SMAD3 can both promote and inhibit apoptosis depending on cell type.
Non-core pleiotropic process.
- term:
id: GO:0043565
label: sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for sequence-specific DNA binding from rat data.
action: ACCEPT
reason: 'Correct. SMAD3 MH1 domain binds specific DNA sequences (SBE: GTCT/AGAC). Crystal structure confirms sequence-specific
binding (PMID:9741623).'
- term:
id: GO:0045429
label: positive regulation of nitric oxide biosynthetic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of nitric oxide biosynthesis from rat data.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of Pol II transcription from rat data.
action: ACCEPT
reason: Correct. SMAD3 activates Pol II transcription. Also supported by IBA and IMP annotations.
- term:
id: GO:0050728
label: negative regulation of inflammatory response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of inflammatory response from mouse data.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 is a key anti-inflammatory pathway. Also supported by NAS (ComplexPortal).
Non-core immune process.
- term:
id: GO:0050776
label: regulation of immune response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for regulation of immune response from mouse data.
action: KEEP_AS_NON_CORE
reason: Valid broad downstream effect. TGF-beta/SMAD3 is critical for immune regulation. Non-core pleiotropic process.
- term:
id: GO:0050821
label: protein stabilization
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for protein stabilization from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect effect. While SMAD3 can affect protein stability through transcriptional regulation of ubiquitin pathway
components, protein stabilization is not a direct function.
- term:
id: GO:0050927
label: positive regulation of positive chemotaxis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of positive chemotaxis from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect downstream effect of TGF-beta signaling. Not a direct SMAD3 function.
- term:
id: GO:0051496
label: positive regulation of stress fiber assembly
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of stress fiber assembly from rat data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0051881
label: regulation of mitochondrial membrane potential
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for regulation of mitochondrial membrane potential from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect downstream effect. Not a direct function of SMAD3 as a transcription factor.
- term:
id: GO:0051894
label: positive regulation of focal adhesion assembly
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of focal adhesion assembly from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect downstream effect of TGF-beta-mediated EMT or cytoskeletal changes. Not a direct SMAD3 function.
- term:
id: GO:0060290
label: transdifferentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for transdifferentiation from rat data.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 drives EMT (a form of transdifferentiation). Non-core pleiotropic process.
- term:
id: GO:0060395
label: SMAD protein signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for SMAD protein signal transduction from rat data.
action: ACCEPT
reason: Correct. Core biological process. Also supported by multiple IBA and IDA annotations.
- term:
id: GO:0061001
label: regulation of dendritic spine morphogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for regulation of dendritic spine morphogenesis from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Very specific neuronal process. Likely indirect TGF-beta pathway effect. No direct evidence for SMAD3-specific
role in dendritic spine morphogenesis in humans.
- term:
id: GO:0061045
label: negative regulation of wound healing
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of wound healing from mouse data.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. UniProt notes SMAD3 has inhibitory effect on wound healing. Non-core tissue-specific
process.
- term:
id: GO:0061629
label: RNA polymerase II-specific DNA-binding transcription factor binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for RNA polymerase II-specific DNA-binding TF binding from mouse data.
action: ACCEPT
reason: Correct. SMAD3 binds other Pol II TFs (c-Jun, c-Fos, FOXH1, etc.). Also supported by IPI annotations.
- term:
id: GO:0061767
label: negative regulation of lung blood pressure
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of lung blood pressure from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Very specific physiological process likely from rat cardiovascular studies. Indirect downstream effect of TGF-beta
signaling.
- term:
id: GO:0071333
label: cellular response to glucose stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for cellular response to glucose stimulus from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect. TGF-beta/SMAD signaling may be modulated by metabolic conditions, but SMAD3 is not a direct glucose
sensor.
- term:
id: GO:0071560
label: cellular response to transforming growth factor beta stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for cellular response to TGF-beta stimulus from rat data.
action: ACCEPT
reason: Correct. Core biological process. SMAD3 is a primary mediator of cellular responses to TGF-beta. Also supported
by IDA (PMID:12902338).
- term:
id: GO:0090263
label: positive regulation of canonical Wnt signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for positive regulation of canonical Wnt signaling pathway from rat data.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0097191
label: extrinsic apoptotic signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for extrinsic apoptotic signaling pathway from rat data.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta can trigger apoptosis through SMAD3-dependent transcriptional programs. Also
supported by IMP (PMID:15334054). Non-core process.
- term:
id: GO:0097305
label: response to alcohol
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for response to alcohol from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Likely from rat liver/fibrosis studies where alcohol induces TGF-beta signaling. Not a direct SMAD3 function.
- term:
id: GO:0098586
label: cellular response to virus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for cellular response to virus from mouse data.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:1903243
label: negative regulation of cardiac muscle hypertrophy in response to stress
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for negative regulation of cardiac muscle hypertrophy from rat data.
action: MARK_AS_OVER_ANNOTATED
reason: Very specific cardiac process. Indirect TGF-beta pathway effect. Not a direct SMAD3 function.
- term:
id: GO:1990841
label: promoter-specific chromatin binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: IEA (Ensembl orthologs) for promoter-specific chromatin binding from mouse data.
action: ACCEPT
reason: Correct. SMAD3 binds chromatin at specific promoters of TGF-beta target genes.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: Nucleoplasm localization (GO_REF:0000052).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: NAS
original_reference_id: PMID:35359452
review:
summary: Regulation of DNA-templated transcription confirmed (PMID:35359452).
action: ACCEPT
reason: Core biological process. SMAD3 is a transcription factor that regulates gene expression.
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: NAS
original_reference_id: PMID:35359452
review:
summary: TGF-beta receptor signaling pathway confirmed (PMID:35359452).
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling.
- term:
id: GO:0032924
label: activin receptor signaling pathway
evidence_type: NAS
original_reference_id: PMID:15150278
review:
summary: Activin receptor signaling pathway confirmed (PMID:15150278).
action: ACCEPT
reason: Core biological process. SMAD3 mediates activin signaling through ACVR1B.
- term:
id: GO:0005634
label: nucleus
evidence_type: IPI
original_reference_id: PMID:20935647
review:
summary: Nucleus localization confirmed (PMID:20935647). SMAD3 translocates to nucleus upon TGF-beta activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IPI
original_reference_id: PMID:20935647
review:
summary: Cytoplasm localization confirmed (PMID:20935647). SMAD3 resides in cytoplasm before activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus.
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:25060702
review:
summary: Regulation of DNA-templated transcription confirmed (PMID:25060702).
action: ACCEPT
reason: Core biological process. SMAD3 is a transcription factor that regulates gene expression.
- term:
id: GO:0031665
label: negative regulation of lipopolysaccharide-mediated signaling pathway
evidence_type: NAS
original_reference_id: PMID:29789615
review:
summary: Negative regulation of LPS-mediated signaling pathway (PMID:29789615). NAS from ComplexPortal.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect reflecting anti-inflammatory role of TGF-beta/SMAD3. Non-core immune process.
- term:
id: GO:0050728
label: negative regulation of inflammatory response
evidence_type: NAS
original_reference_id: PMID:27060871
review:
summary: Negative regulation of inflammatory response (PMID:27060871). NAS from ComplexPortal.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 is a key anti-inflammatory pathway. Non-core immune process.
- term:
id: GO:0071635
label: negative regulation of transforming growth factor beta production
evidence_type: NAS
original_reference_id: PMID:20935647
review:
summary: Negative regulation of TGF-beta production (PMID:20935647). NAS from ComplexPortal.
action: KEEP_AS_NON_CORE
reason: Valid feedback regulation. SMAD3 can modulate TGF-beta expression as part of signaling feedback. Non-core regulatory
process.
- term:
id: GO:0061450
label: trophoblast cell migration
evidence_type: IDA
original_reference_id: PMID:34432647
review:
summary: Trophoblast cell migration (PMID:34432647).
action: KEEP_AS_NON_CORE
reason: Specific developmental process. TGF-beta/SMAD3 promotes trophoblast migration. Non-core tissue-specific process.
- term:
id: GO:0045596
label: negative regulation of cell differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Negative regulation of cell differentiation (GO_REF:0000024). ISS from mouse ortholog.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 can inhibit differentiation in certain contexts. Non-core pleiotropic
process.
- term:
id: GO:0060391
label: positive regulation of SMAD protein signal transduction
evidence_type: IMP
original_reference_id: PMID:15107418
review:
summary: Positive regulation of SMAD protein signal transduction (PMID:15107418).
action: ACCEPT
reason: SMAD3 positively promotes SMAD signal transduction as an R-SMAD that forms complexes with SMAD4.
- term:
id: GO:0097190
label: apoptotic signaling pathway
evidence_type: IMP
original_reference_id: PMID:15107418
review:
summary: Apoptotic signaling pathway (PMID:15107418).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 can trigger apoptosis in certain contexts. Non-core pleiotropic process.
- term:
id: GO:0030279
label: negative regulation of ossification
evidence_type: IDA
original_reference_id: PMID:22155034
review:
summary: Negative regulation of ossification (PMID:22155034).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. UniProt notes SMAD3 inhibits early healing of bone fractures. Non-core tissue-specific
process.
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IMP
original_reference_id: PMID:8774881
review:
summary: TGF-beta receptor signaling pathway confirmed (PMID:8774881).
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling.
- term:
id: GO:0060395
label: SMAD protein signal transduction
evidence_type: IMP
original_reference_id: PMID:30729664
review:
summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:30729664).
action: ACCEPT
reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction.
- term:
id: GO:1901203
label: positive regulation of extracellular matrix assembly
evidence_type: IMP
original_reference_id: PMID:30729664
review:
summary: Positive regulation of extracellular matrix assembly (PMID:30729664).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 transcriptionally activates ECM genes (collagen, fibronectin). Non-core
but well-documented in fibrosis context.
- term:
id: GO:1902895
label: positive regulation of miRNA transcription
evidence_type: IMP
original_reference_id: PMID:30729664
review:
summary: Positive regulation of miRNA transcription (PMID:30729664).
action: KEEP_AS_NON_CORE
reason: Valid specific function. SMAD3 regulates miRNA transcription at specific loci. Non-core regulatory process.
- term:
id: GO:1990776
label: response to angiotensin
evidence_type: IMP
original_reference_id: PMID:30729664
review:
summary: Response to angiotensin (PMID:30729664). Acts upstream of.
action: KEEP_AS_NON_CORE
reason: TGF-beta/SMAD3 signaling cross-talks with angiotensin pathways in cardiovascular/fibrotic contexts. Non-core.
- term:
id: GO:0060395
label: SMAD protein signal transduction
evidence_type: IDA
original_reference_id: PMID:9732876
review:
summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:9732876).
action: ACCEPT
reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction.
- term:
id: GO:0031625
label: ubiquitin protein ligase binding
evidence_type: IPI
original_reference_id: PMID:15781469
review:
summary: Ubiquitin protein ligase binding confirmed. SMAD3 interacts with E3 ligases including SMURF2, NEDD4L, STUB1/CHIP
(PMID:15781469).
action: ACCEPT
reason: Well-supported. SMAD3 is a substrate of multiple E3 ubiquitin ligases that regulate its stability and function.
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:9311995
review:
summary: TGF-beta receptor signaling pathway confirmed (PMID:9311995).
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling.
- term:
id: GO:0060395
label: SMAD protein signal transduction
evidence_type: IDA
original_reference_id: PMID:9311995
review:
summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:9311995).
action: ACCEPT
reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction.
- term:
id: GO:0001222
label: transcription corepressor binding
evidence_type: IPI
original_reference_id: PMID:14612439
review:
summary: Transcription corepressor binding confirmed. SMAD3 interacts with corepressors including Ski, SnoN, TGIF (PMID:14612439).
action: ACCEPT
reason: Well-supported. SMAD3 recruits transcriptional corepressors at certain target genes.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:10823886
review:
summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:10823886).
action: ACCEPT
reason: Core molecular function of SMAD3. Directly binds DNA and regulates transcription.
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:10823886
review:
summary: TGF-beta receptor signaling pathway confirmed (PMID:10823886).
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling.
- term:
id: GO:0060395
label: SMAD protein signal transduction
evidence_type: IDA
original_reference_id: PMID:10823886
review:
summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:10823886).
action: ACCEPT
reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction.
- term:
id: GO:0060395
label: SMAD protein signal transduction
evidence_type: IDA
original_reference_id: PMID:9111321
review:
summary: SMAD protein signal transduction confirmed by experimental evidence (PMID:9111321).
action: ACCEPT
reason: Core biological process. SMAD3 is a principal mediator of SMAD signal transduction.
- term:
id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
evidence_type: IMP
original_reference_id: PMID:32141990
review:
summary: Cis-regulatory region sequence-specific DNA binding confirmed (PMID:32141990).
action: ACCEPT
reason: Core molecular function. SMAD3 binds SBE sequences in cis-regulatory regions.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IMP
original_reference_id: PMID:32141990
review:
summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:32141990).
action: ACCEPT
reason: Core molecular function of SMAD3. Directly binds DNA and regulates transcription.
- term:
id: GO:1902894
label: negative regulation of miRNA transcription
evidence_type: IMP
original_reference_id: PMID:32141990
review:
summary: Negative regulation of miRNA transcription (PMID:32141990).
action: KEEP_AS_NON_CORE
reason: Valid specific function. SMAD3 can also repress miRNA transcription at certain loci. Non-core regulatory process.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:24378993
review:
summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding confirmed (PMID:24378993).
action: ACCEPT
reason: Core molecular function. SMAD3 binds SBEs in Pol II-regulated cis-regulatory regions.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IDA
original_reference_id: PMID:24378993
review:
summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:24378993).
action: ACCEPT
reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IMP
original_reference_id: PMID:24378993
review:
summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:24378993).
action: ACCEPT
reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes.
- term:
id: GO:0010629
label: negative regulation of gene expression
evidence_type: IMP
original_reference_id: PMID:24378993
review:
summary: Negative regulation of gene expression (PMID:24378993).
action: ACCEPT
reason: Valid. SMAD3 can repress gene expression at certain loci through corepressor recruitment.
- term:
id: GO:1902895
label: positive regulation of miRNA transcription
evidence_type: IDA
original_reference_id: PMID:24378993
review:
summary: Positive regulation of miRNA transcription (PMID:24378993).
action: KEEP_AS_NON_CORE
reason: Valid specific function. SMAD3 regulates miRNA transcription at specific loci. Non-core regulatory process.
- term:
id: GO:1902895
label: positive regulation of miRNA transcription
evidence_type: IMP
original_reference_id: PMID:24378993
review:
summary: Positive regulation of miRNA transcription (PMID:24378993).
action: KEEP_AS_NON_CORE
reason: Valid specific function. SMAD3 regulates miRNA transcription at specific loci. Non-core regulatory process.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2179276
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2179276).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15051726
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15051726). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29899023
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:29899023). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: ISS
original_reference_id: PMID:24964035
review:
summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:24964035).
action: ACCEPT
reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IDA
original_reference_id: PMID:25605017
review:
summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:25605017).
action: ACCEPT
reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes.
- term:
id: GO:0032810
label: sterol response element binding
evidence_type: IGI
original_reference_id: PMID:25605017
review:
summary: Sterol response element binding. SMAD3 binds SRE in IGI with TGF-beta1 (PMID:25605017).
action: KEEP_AS_NON_CORE
reason: Specialized binding activity at specific genomic loci. Non-core but documented.
- term:
id: GO:0061629
label: RNA polymerase II-specific DNA-binding transcription factor binding
evidence_type: IPI
original_reference_id: PMID:9732876
review:
summary: SMAD3 binds Pol II-specific DNA-binding TFs including c-Jun, c-Fos, PAX6 (PMID:9732876).
action: ACCEPT
reason: Core molecular function. SMAD3 cooperates with other TFs at composite promoter elements.
supported_by:
- reference_id: PMID:9732876
supporting_text: 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
- term:
id: GO:0140297
label: DNA-binding transcription factor binding
evidence_type: IPI
original_reference_id: PMID:21828274
review:
summary: DNA-binding transcription factor binding. SMAD3 binds FOXH1 (PMID:21828274).
action: ACCEPT
reason: Well-supported. SMAD3 cooperates with multiple DNA-binding TFs.
- term:
id: GO:0016922
label: nuclear receptor binding
evidence_type: IPI
original_reference_id: PMID:31023188
review:
summary: Nuclear receptor binding. SMAD3 binds PPARgamma (PMID:31023188).
action: ACCEPT
reason: Well-documented interaction. SMAD3 interacts with nuclear receptors as part of transcriptional cross-talk.
- term:
id: GO:0008285
label: negative regulation of cell population proliferation
evidence_type: IMP
original_reference_id: PMID:14555988
review:
summary: Negative regulation of cell population proliferation confirmed (PMID:14555988).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 mediates growth arrest through CDK inhibitor induction. Non-core but important
pleiotropic process.
- term:
id: GO:1902893
label: regulation of miRNA transcription
evidence_type: IC
original_reference_id: PMID:25605017
review:
summary: Regulation of miRNA transcription (PMID:25605017).
action: KEEP_AS_NON_CORE
reason: Valid. SMAD3 regulates miRNA transcription. Parent term of both positive and negative regulation annotations.
Non-core.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:28467929
review:
summary: Negative regulation of transcription by Pol II confirmed (PMID:28467929). SMAD3 can repress transcription.
action: ACCEPT
reason: Valid. SMAD3 acts as transcriptional repressor at certain loci with Ski/SnoN/TGIF cofactors.
- term:
id: GO:0001217
label: DNA-binding transcription repressor activity
evidence_type: IDA
original_reference_id: PMID:28467929
review:
summary: DNA-binding transcription repressor activity confirmed (PMID:28467929). SMAD3 can also repress transcription
at certain loci.
action: ACCEPT
reason: Valid. SMAD3 acts as both activator and repressor depending on cofactor context (Ski/SnoN, TGIF for repression).
- term:
id: GO:0003677
label: DNA binding
evidence_type: IDA
original_reference_id: PMID:28467929
review:
summary: DNA binding confirmed by direct assay (PMID:28467929).
action: ACCEPT
reason: Core molecular function. SMAD3 MH1 domain directly binds DNA.
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:28467929
review:
summary: TGF-beta receptor signaling pathway confirmed (PMID:28467929).
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9731111
review:
summary: Cytosol localization (Reactome:R-HSA-9731111).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IMP
original_reference_id: PMID:26311719
review:
summary: DNA-binding transcription activator activity, Pol II-specific, confirmed (PMID:26311719).
action: ACCEPT
reason: Core molecular function. SMAD3 activates transcription of TGF-beta target genes.
- term:
id: GO:1902895
label: positive regulation of miRNA transcription
evidence_type: IMP
original_reference_id: PMID:26311719
review:
summary: Positive regulation of miRNA transcription (PMID:26311719).
action: KEEP_AS_NON_CORE
reason: Valid specific function. SMAD3 regulates miRNA transcription at specific loci. Non-core regulatory process.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23723426
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:23723426). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005634
label: nucleus
evidence_type: IGI
original_reference_id: PMID:23723426
review:
summary: Nucleus localization confirmed (PMID:23723426). SMAD3 translocates to nucleus upon TGF-beta activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation.
- term:
id: GO:0005829
label: cytosol
evidence_type: IGI
original_reference_id: PMID:23723426
review:
summary: Cytosol localization (PMID:23723426).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:18832382
review:
summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding confirmed (PMID:18832382).
action: ACCEPT
reason: Core molecular function. SMAD3 binds SBEs in Pol II-regulated cis-regulatory regions.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:21145499
review:
summary: Nucleus localization confirmed (PMID:21145499). SMAD3 translocates to nucleus upon TGF-beta activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:21145499
review:
summary: Cytoplasm localization confirmed (PMID:21145499). SMAD3 resides in cytoplasm before activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:31582430
review:
summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding confirmed (PMID:31582430).
action: ACCEPT
reason: Core molecular function. SMAD3 binds SBEs in Pol II-regulated cis-regulatory regions.
- term:
id: GO:0001223
label: transcription coactivator binding
evidence_type: IPI
original_reference_id: PMID:16777850
review:
summary: Transcription coactivator binding confirmed. SMAD3 interacts with coactivators including p300/CBP, ZMIZ1 (PMID:16777850).
action: ACCEPT
reason: Well-supported. SMAD3 linker region and MH2 domain recruit p300/CBP coactivators.
- term:
id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
evidence_type: IC
original_reference_id: PMID:21828274
review:
summary: Cis-regulatory region sequence-specific DNA binding confirmed (PMID:21828274).
action: ACCEPT
reason: Core molecular function. SMAD3 binds SBE sequences in cis-regulatory regions.
- term:
id: GO:0000785
label: chromatin
evidence_type: ISA
original_reference_id: GO_REF:0000113
review:
summary: Chromatin localization (GO_REF:0000113). SMAD3 is found at chromatin at TGF-beta target gene loci.
action: ACCEPT
reason: Correct. ChIP studies confirm SMAD3 binding to chromatin at enhancer/promoter regions.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: ISA
original_reference_id: GO_REF:0000113
review:
summary: ISA from TFClass database for DNA-binding TF activity Pol II-specific.
action: ACCEPT
reason: Correct. SMAD3 is classified as a TF in TFClass. Also supported by IDA and IBA.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: IDA
original_reference_id: PMID:21947082
review:
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.'
action: ACCEPT
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.
- term:
id: GO:0042307
label: positive regulation of protein import into nucleus
evidence_type: NAS
original_reference_id: PMID:15799969
review:
summary: Positive regulation of protein import into nucleus (PMID:15799969).
action: ACCEPT
reason: SMAD3 promotes nuclear import of the SMAD2/3-SMAD4 complex. Part of core signaling mechanism.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25556234
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:25556234). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:18548003
review:
summary: TGF-beta receptor signaling pathway confirmed (PMID:18548003).
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling.
- term:
id: GO:0017151
label: DEAD/H-box RNA helicase binding
evidence_type: IPI
original_reference_id: PMID:18548003
review:
summary: DEAD/H-box RNA helicase binding. SMAD3 interacts with DDX5 (p68) (PMID:18548003).
action: ACCEPT
reason: Documented interaction. DDX5/p68 modulates SMAD3-dependent transcription.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24613385
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:24613385). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0031962
label: nuclear mineralocorticoid receptor binding
evidence_type: IPI
original_reference_id: PMID:12902338
review:
summary: Nuclear mineralocorticoid receptor binding. SMAD3 interacts with NR3C2 (PMID:12902338).
action: KEEP_AS_NON_CORE
reason: Documented interaction representing transcriptional cross-talk between TGF-beta and mineralocorticoid signaling.
- term:
id: GO:0035259
label: nuclear glucocorticoid receptor binding
evidence_type: IPI
original_reference_id: PMID:12902338
review:
summary: Nuclear glucocorticoid receptor binding. SMAD3 interacts with NR3C1 (PMID:12902338).
action: KEEP_AS_NON_CORE
reason: Documented interaction representing transcriptional cross-talk between TGF-beta and glucocorticoid signaling.
- term:
id: GO:0071560
label: cellular response to transforming growth factor beta stimulus
evidence_type: IDA
original_reference_id: PMID:12902338
review:
summary: Cellular response to TGF-beta stimulus confirmed (PMID:12902338).
action: ACCEPT
reason: Core biological process. SMAD3 is a primary mediator of cellular TGF-beta responses.
- term:
id: GO:0045429
label: positive regulation of nitric oxide biosynthetic process
evidence_type: IDA
original_reference_id: PMID:27038547
review:
summary: Positive regulation of nitric oxide biosynthetic process (PMID:27038547).
action: KEEP_AS_NON_CORE
reason: Specific downstream effect in certain cell types. Non-core pleiotropic process.
- term:
id: GO:0051481
label: negative regulation of cytosolic calcium ion concentration
evidence_type: IDA
original_reference_id: PMID:27038547
review:
summary: Negative regulation of cytosolic calcium ion concentration (PMID:27038547).
action: MARK_AS_OVER_ANNOTATED
reason: Indirect downstream effect. SMAD3 as a transcription factor does not directly regulate calcium concentrations.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6781764
review:
summary: Cytosol localization (Reactome:R-HSA-6781764).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:25893292
review:
summary: Nucleus localization confirmed (PMID:25893292). SMAD3 translocates to nucleus upon TGF-beta activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation.
- term:
id: GO:0045599
label: negative regulation of fat cell differentiation
evidence_type: IDA
original_reference_id: PMID:19816956
review:
summary: Negative regulation of fat cell differentiation (PMID:19816956).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 inhibits adipogenesis. Non-core tissue-specific process.
- term:
id: GO:1901203
label: positive regulation of extracellular matrix assembly
evidence_type: IDA
original_reference_id: PMID:21307346
review:
summary: Positive regulation of extracellular matrix assembly (PMID:21307346).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 transcriptionally activates ECM genes (collagen, fibronectin). Non-core
but well-documented in fibrosis context.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:16007207
review:
summary: Nucleus localization confirmed (PMID:16007207). SMAD3 translocates to nucleus upon TGF-beta activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding confirmed (PMID:21947082).
action: ACCEPT
reason: Core molecular function. SMAD3 binds SBEs in Pol II-regulated cis-regulatory regions.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: Regulation of transcription by RNA polymerase II confirmed (PMID:21947082).
action: ACCEPT
reason: Core biological process. SMAD3 regulates Pol II transcription at target genes.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:14555988
review:
summary: Positive regulation of Pol II transcription confirmed (PMID:14555988).
action: ACCEPT
reason: Core biological process. SMAD3 activates transcription of TGF-beta responsive genes.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IDA
original_reference_id: PMID:21307346
review:
summary: Positive regulation of gene expression (PMID:21307346).
action: ACCEPT
reason: Core biological process. SMAD3 activates expression of TGF-beta target genes.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20129061
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:20129061). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24627487
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:24627487). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0070412
label: R-SMAD binding
evidence_type: IPI
original_reference_id: PMID:20129061
review:
summary: R-SMAD binding confirmed. SMAD3 binds other R-SMADs (SMAD2) and itself (PMID:20129061).
action: ACCEPT
reason: Well-supported interaction. SMAD3 interacts with SMAD2 as part of the TGF-beta signaling pathway.
supported_by:
- reference_id: PMID:9311995
supporting_text: we observed TbetaR-activation-dependent interaction between Smad2 and Smad3
- term:
id: GO:0000785
label: chromatin
evidence_type: IDA
original_reference_id: PMID:21828274
review:
summary: Chromatin localization (PMID:21828274). SMAD3 is found at chromatin at TGF-beta target gene loci.
action: ACCEPT
reason: Correct. ChIP studies confirm SMAD3 binding to chromatin at enhancer/promoter regions.
- term:
id: GO:0043425
label: bHLH transcription factor binding
evidence_type: IPI
original_reference_id: PMID:21828274
review:
summary: bHLH transcription factor binding. SMAD3 binds HEB/TCF12 (PMID:21828274).
action: ACCEPT
reason: Documented interaction between SMAD3 and bHLH TFs at target gene promoters.
- term:
id: GO:0071144
label: heteromeric SMAD protein complex
evidence_type: IDA
original_reference_id: PMID:21828274
review:
summary: Heteromeric SMAD protein complex confirmed (PMID:21828274).
action: ACCEPT
reason: Core cellular component. SMAD3/SMAD4 heterotrimer is the functional transcriptional complex.
- term:
id: GO:0097191
label: extrinsic apoptotic signaling pathway
evidence_type: IMP
original_reference_id: PMID:15334054
review:
summary: Extrinsic apoptotic signaling pathway (PMID:15334054).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. Non-core pleiotropic process.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2176475
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2176475).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2176491
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2176491).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2176502
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2176502).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2176503
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2176503).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2179274
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2179274).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1535903
review:
summary: Nucleoplasm localization (Reactome:R-HSA-1535903).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-173481
review:
summary: Nucleoplasm localization (Reactome:R-HSA-173481).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-173488
review:
summary: Nucleoplasm localization (Reactome:R-HSA-173488).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-173545
review:
summary: Nucleoplasm localization (Reactome:R-HSA-173545).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-209055
review:
summary: Nucleoplasm localization (Reactome:R-HSA-209055).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2106579
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2106579).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2127257
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2127257).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2186607
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2186607).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2186643
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2186643).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187309
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2187309).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187325
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2187325).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187330
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2187330).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187388
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2187388).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-870449
review:
summary: Nucleoplasm localization (Reactome:R-HSA-870449).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-870538
review:
summary: Nucleoplasm localization (Reactome:R-HSA-870538).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8878143
review:
summary: Nucleoplasm localization (Reactome:R-HSA-8878143).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8878178
review:
summary: Nucleoplasm localization (Reactome:R-HSA-8878178).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8952226
review:
summary: Nucleoplasm localization (Reactome:R-HSA-8952226).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9617996
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9617996).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9618004
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9618004).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9618021
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9618021).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9733207
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9733207).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9733247
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9733247).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9736959
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9736959).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9736970
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9736970).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9736979
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9736979).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9736984
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9736984).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9736992
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9736992).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9737710
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9737710).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9823952
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9823952).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9823959
review:
summary: Nucleoplasm localization (Reactome:R-HSA-9823959).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-NUL-2186736
review:
summary: Nucleoplasm localization (Reactome:R-NUL-2186736).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-NUL-2186755
review:
summary: Nucleoplasm localization (Reactome:R-NUL-2186755).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-NUL-9625758
review:
summary: Nucleoplasm localization (Reactome:R-NUL-9625758).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-3315483
review:
summary: Cytosol localization (Reactome:R-HSA-3315483).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187395
review:
summary: Nucleoplasm localization (Reactome:R-HSA-2187395).
action: ACCEPT
reason: Correct. SMAD3 is found in nucleoplasm when in the nucleus. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1549526
review:
summary: Cytosol localization (Reactome:R-HSA-1549526).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-170847
review:
summary: Cytosol localization (Reactome:R-HSA-170847).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-170850
review:
summary: Cytosol localization (Reactome:R-HSA-170850).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-170868
review:
summary: Cytosol localization (Reactome:R-HSA-170868).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-173488
review:
summary: Cytosol localization (Reactome:R-HSA-173488).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2031355
review:
summary: Cytosol localization (Reactome:R-HSA-2031355).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2106579
review:
summary: Cytosol localization (Reactome:R-HSA-2106579).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187355
review:
summary: Cytosol localization (Reactome:R-HSA-2187355).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187401
review:
summary: Cytosol localization (Reactome:R-HSA-2187401).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187405
review:
summary: Cytosol localization (Reactome:R-HSA-2187405).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-3311014
review:
summary: Cytosol localization (Reactome:R-HSA-3311014).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9008928
review:
summary: Cytosol localization (Reactome:R-HSA-9008928).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9009910
review:
summary: Cytosol localization (Reactome:R-HSA-9009910).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: Cis-regulatory region sequence-specific DNA binding confirmed (PMID:21947082).
action: ACCEPT
reason: Core molecular function. SMAD3 binds SBE sequences in cis-regulatory regions.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:21947082).
action: ACCEPT
reason: Core molecular function of SMAD3. Directly binds DNA and regulates transcription.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21947082
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21947082). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: Nucleus localization confirmed (PMID:21947082). SMAD3 translocates to nucleus upon TGF-beta activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation.
- term:
id: GO:0005667
label: transcription regulator complex
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: Transcription regulator complex confirmed (PMID:21947082). SMAD3 forms complexes with SMAD4 and cofactors.
action: ACCEPT
reason: Correct. SMAD3/SMAD4 heteromeric complexes function as transcription regulator complexes.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: Cytoplasm localization confirmed (PMID:21947082). SMAD3 resides in cytoplasm before activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus.
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: TGF-beta receptor signaling pathway confirmed (PMID:21947082).
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling.
- term:
id: GO:0071141
label: SMAD protein complex
evidence_type: IDA
original_reference_id: PMID:21947082
review:
summary: SMAD protein complex confirmed (PMID:21947082).
action: ACCEPT
reason: Correct. SMAD3 forms SMAD protein complexes including homo-oligomers and hetero-complexes with SMAD4.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21307346
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:21307346). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0010718
label: positive regulation of epithelial to mesenchymal transition
evidence_type: IDA
original_reference_id: PMID:21307346
review:
summary: Positive regulation of EMT (PMID:21307346).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 is a major driver of EMT. Non-core but well-documented process.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19289081
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19289081). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9865696
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:9865696). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9892009
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:9892009). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0032924
label: activin receptor signaling pathway
evidence_type: IMP
original_reference_id: PMID:15150278
review:
summary: Activin receptor signaling pathway confirmed (PMID:15150278).
action: ACCEPT
reason: Core biological process. SMAD3 mediates activin signaling through ACVR1B.
- term:
id: GO:0038092
label: nodal signaling pathway
evidence_type: IMP
original_reference_id: PMID:15150278
review:
summary: Nodal signaling pathway (PMID:15150278).
action: ACCEPT
reason: SMAD3 also mediates Nodal signaling, which uses the same R-SMAD pathway as activin/TGF-beta.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-170835
review:
summary: Cytosol localization (Reactome:R-HSA-170835).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187358
review:
summary: Cytosol localization (Reactome:R-HSA-2187358).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187368
review:
summary: Cytosol localization (Reactome:R-HSA-2187368).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187375
review:
summary: Cytosol localization (Reactome:R-HSA-2187375).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187382
review:
summary: Cytosol localization (Reactome:R-HSA-2187382).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2187395
review:
summary: Cytosol localization (Reactome:R-HSA-2187395).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-3656523
review:
summary: Cytosol localization (Reactome:R-HSA-3656523).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9008692
review:
summary: Cytosol localization (Reactome:R-HSA-9008692).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9727922
review:
summary: Cytosol localization (Reactome:R-HSA-9727922).
action: ACCEPT
reason: Correct. SMAD3 is found in the cytosol before activation. Multiple Reactome pathways confirm.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10681527
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:10681527). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0043130
label: ubiquitin binding
evidence_type: IDA
original_reference_id: PMID:18794808
review:
summary: Ubiquitin binding confirmed (PMID:18794808). SMAD3 is subject to monoubiquitination that regulates DNA binding.
action: ACCEPT
reason: Well-supported by PMID:18794808 and PMID:21947082. Monoubiquitination of SMAD3 prevents DNA binding; USP15 deubiquitination
restores it.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17469184
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:17469184). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18832382
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:18832382). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:18832382
review:
summary: Positive regulation of Pol II transcription confirmed (PMID:18832382).
action: ACCEPT
reason: Core biological process. SMAD3 activates transcription of TGF-beta responsive genes.
- term:
id: GO:0071141
label: SMAD protein complex
evidence_type: IDA
original_reference_id: PMID:18832382
review:
summary: SMAD protein complex confirmed (PMID:18832382).
action: ACCEPT
reason: Correct. SMAD3 forms SMAD protein complexes including homo-oligomers and hetero-complexes with SMAD4.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15588252
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15588252). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0008270
label: zinc ion binding
evidence_type: IDA
original_reference_id: PMID:12686552
review:
summary: Zinc ion binding confirmed (PMID:12686552). SMAD3 MH1 domain coordinates zinc via Cys and His residues.
action: ACCEPT
reason: Crystal structure confirms zinc coordination in MH1 domain essential for DNA binding (PMID:12686552).
- term:
id: GO:0019902
label: phosphatase binding
evidence_type: IPI
original_reference_id: PMID:16751101
review:
summary: Phosphatase binding. SMAD3 binds PPM1A (PMID:16751101).
action: ACCEPT
reason: Well-documented. PPM1A dephosphorylates SMAD3 C-terminal SSXS motif to terminate TGF-beta signaling (PMID:16751101).
- term:
id: GO:0061629
label: RNA polymerase II-specific DNA-binding transcription factor binding
evidence_type: IPI
original_reference_id: PMID:17251190
review:
summary: SMAD3 binds Pol II-specific DNA-binding TFs including c-Jun, c-Fos, PAX6 (PMID:17251190).
action: ACCEPT
reason: Core molecular function. SMAD3 cooperates with other TFs at composite promoter elements.
supported_by:
- reference_id: PMID:9732876
supporting_text: 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
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18568018
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:18568018). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0031625
label: ubiquitin protein ligase binding
evidence_type: IPI
original_reference_id: PMID:11278251
review:
summary: Ubiquitin protein ligase binding confirmed. SMAD3 interacts with E3 ligases including SMURF2, NEDD4L, STUB1/CHIP
(PMID:11278251).
action: ACCEPT
reason: Well-supported. SMAD3 is a substrate of multiple E3 ubiquitin ligases that regulate its stability and function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15897867
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15897867). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17099224
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:17099224). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15647271
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:15647271). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005637
label: nuclear inner membrane
evidence_type: IDA
original_reference_id: PMID:15647271
review:
summary: Nuclear inner membrane localization (PMID:15647271). SMAD3 co-localizes with LEMD3/MAN1.
action: KEEP_AS_NON_CORE
reason: SMAD3 interacts with LEMD3/MAN1 at the nuclear inner membrane, which sequesters SMAD3 to antagonize signaling.
Specialized localization.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19049980
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19049980). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0019901
label: protein kinase binding
evidence_type: IPI
original_reference_id: PMID:12874272
review:
summary: Protein kinase binding. SMAD3 binds CDK8/CDK9 (PMID:12874272).
action: ACCEPT
reason: SMAD3 interacts with kinases including CDK8/9 that phosphorylate its linker region.
- term:
id: GO:0010718
label: positive regulation of epithelial to mesenchymal transition
evidence_type: IMP
original_reference_id: PMID:18505915
review:
summary: Positive regulation of EMT (PMID:18505915).
action: KEEP_AS_NON_CORE
reason: Valid downstream effect. TGF-beta/SMAD3 is a major driver of EMT. Non-core but well-documented process.
- term:
id: GO:0045216
label: cell-cell junction organization
evidence_type: IMP
original_reference_id: PMID:18505915
review:
summary: Cell-cell junction organization (PMID:18505915). Related to EMT.
action: KEEP_AS_NON_CORE
reason: Valid downstream effect related to TGF-beta-induced EMT. Non-core pleiotropic process.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16200078
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:16200078). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17292623
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:17292623). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0070410
label: co-SMAD binding
evidence_type: IPI
original_reference_id: PMID:8774881
review:
summary: co-SMAD binding confirmed. SMAD3 directly binds SMAD4 via MH2 domain to form the transcriptionally active heteromeric
complex (PMID:8774881).
action: ACCEPT
reason: Core molecular function. SMAD3-SMAD4 interaction is the central event in TGF-beta signal transduction.
supported_by:
- reference_id: PMID:9311995
supporting_text: Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells
- term:
id: GO:0070410
label: co-SMAD binding
evidence_type: IPI
original_reference_id: PMID:9111321
review:
summary: co-SMAD binding confirmed. SMAD3 directly binds SMAD4 via MH2 domain to form the transcriptionally active heteromeric
complex (PMID:9111321).
action: ACCEPT
reason: Core molecular function. SMAD3-SMAD4 interaction is the central event in TGF-beta signal transduction.
supported_by:
- reference_id: PMID:9311995
supporting_text: Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells
- term:
id: GO:0070410
label: co-SMAD binding
evidence_type: IPI
original_reference_id: PMID:9311995
review:
summary: co-SMAD binding confirmed. SMAD3 directly binds SMAD4 via MH2 domain to form the transcriptionally active heteromeric
complex (PMID:9311995).
action: ACCEPT
reason: Core molecular function. SMAD3-SMAD4 interaction is the central event in TGF-beta signal transduction.
supported_by:
- reference_id: PMID:9311995
supporting_text: Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells
- term:
id: GO:0070410
label: co-SMAD binding
evidence_type: IPI
original_reference_id: PMID:9732876
review:
summary: co-SMAD binding confirmed. SMAD3 directly binds SMAD4 via MH2 domain to form the transcriptionally active heteromeric
complex (PMID:9732876).
action: ACCEPT
reason: Core molecular function. SMAD3-SMAD4 interaction is the central event in TGF-beta signal transduction.
supported_by:
- reference_id: PMID:9311995
supporting_text: Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells
- term:
id: GO:0070412
label: R-SMAD binding
evidence_type: IPI
original_reference_id: PMID:9311995
review:
summary: R-SMAD binding confirmed. SMAD3 binds other R-SMADs (SMAD2) and itself (PMID:9311995).
action: ACCEPT
reason: Well-supported interaction. SMAD3 interacts with SMAD2 as part of the TGF-beta signaling pathway.
supported_by:
- reference_id: PMID:9311995
supporting_text: we observed TbetaR-activation-dependent interaction between Smad2 and Smad3
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: IDA
original_reference_id: PMID:9732876
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:9732876
supporting_text: 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.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:9732876
review:
summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:9732876).
action: ACCEPT
reason: Core molecular function of SMAD3. Directly binds DNA and regulates transcription.
- term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:9732876
review:
summary: TGF-beta receptor signaling pathway confirmed (PMID:9732876).
action: ACCEPT
reason: Core biological process. SMAD3 is phosphorylated by TGFBR1 and is essential for canonical TGF-beta signaling.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:9732876
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:9732876
supporting_text: 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.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:9111321
qualifier: contributes_to
review:
summary: DNA-binding transcription factor activity confirmed by experimental evidence (PMID:9111321).
action: ACCEPT
reason: Core molecular function of SMAD3. Directly binds DNA and regulates transcription.
- term:
id: GO:0005160
label: transforming growth factor beta receptor binding
evidence_type: IPI
original_reference_id: PMID:9311995
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:9311995
supporting_text: Smad2 and Smad3 interacted with the kinase-deficient TGF-beta type I receptor (TbetaR)-I after it was
phosphorylated by TbetaR-II kinase.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:9311995
review:
summary: Nucleus localization confirmed (PMID:9311995). SMAD3 translocates to nucleus upon TGF-beta activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:9311995
review:
summary: Cytoplasm localization confirmed (PMID:9311995). SMAD3 resides in cytoplasm before activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus.
- term:
id: GO:0031053
label: primary miRNA processing
evidence_type: TAS
original_reference_id: PMID:19018011
review:
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).
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0042060
label: wound healing
evidence_type: TAS
original_reference_id: PMID:19018011
review:
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).
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:9111321
review:
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).
action: ACCEPT
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.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:9311995
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:9311995
supporting_text: 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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19122240
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:19122240). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0031625
label: ubiquitin protein ligase binding
evidence_type: IPI
original_reference_id: PMID:19122240
review:
summary: Ubiquitin protein ligase binding confirmed. SMAD3 interacts with E3 ligases including SMURF2, NEDD4L, STUB1/CHIP
(PMID:19122240).
action: ACCEPT
reason: Well-supported. SMAD3 is a substrate of multiple E3 ubiquitin ligases that regulate its stability and function.
- term:
id: GO:0006955
label: immune response
evidence_type: IMP
original_reference_id: PMID:16886151
review:
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).
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11274402
review:
summary: Protein binding annotation from high-throughput or targeted interaction study (PMID:11274402). SMAD3 interacts
with numerous proteins as a signaling hub.
action: REMOVE
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.'
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:14555988
review:
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).
action: ACCEPT
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.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:8774881
review:
summary: Negative regulation of transcription by Pol II confirmed (PMID:8774881). SMAD3 can repress transcription.
action: ACCEPT
reason: Valid. SMAD3 acts as transcriptional repressor at certain loci with Ski/SnoN/TGIF cofactors.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:8774881
review:
summary: Positive regulation of Pol II transcription confirmed (PMID:8774881).
action: ACCEPT
reason: Core biological process. SMAD3 activates transcription of TGF-beta responsive genes.
- term:
id: GO:0001666
label: response to hypoxia
evidence_type: IMP
original_reference_id: PMID:12411310
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0032909
label: regulation of transforming growth factor beta2 production
evidence_type: IMP
original_reference_id: PMID:12411310
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:12446380
review:
summary: Nucleus localization confirmed (PMID:12446380). SMAD3 translocates to nucleus upon TGF-beta activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 accumulates in nucleus after TGF-beta-induced phosphorylation.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:12446380
review:
summary: Cytoplasm localization confirmed (PMID:12446380). SMAD3 resides in cytoplasm before activation.
action: ACCEPT
reason: Core cellular localization. SMAD3 shuttles between cytoplasm and nucleus.
- term:
id: GO:0030308
label: negative regulation of cell growth
evidence_type: IDA
original_reference_id: PMID:8774881
review:
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).
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:8774881
supporting_text: 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.
- term:
id: GO:0042803
label: protein homodimerization activity
evidence_type: IPI
original_reference_id: PMID:8774881
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:8774881
supporting_text: hMAD-3 and -4 synergized to induce strong ligand-independent TGF-beta-like responses.
- term:
id: GO:0043235
label: receptor complex
evidence_type: IMP
original_reference_id: PMID:8774881
review:
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).
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:8774881
supporting_text: hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex.
- term:
id: GO:0043565
label: sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:10823886
review:
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).'
action: ACCEPT
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.
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence
similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000113
title: Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass
database
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:10681527
title: Identification and characterization of a PDZ protein that interacts with activin type II receptors.
findings: []
- id: PMID:10823886
title: Transforming growth factor beta -inducible independent binding of SMAD to the Smad7 promoter.
findings: []
- id: PMID:11274402
title: Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling.
findings: []
- id: PMID:11278251
title: Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation.
findings: []
- id: PMID:11278756
title: Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription.
findings: []
- id: PMID:11387212
title: The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway.
findings: []
- id: PMID:12154125
title: Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control.
findings: []
- id: PMID:12411310
title: Cellular response to hypoxia involves signaling via Smad proteins.
findings: []
- id: PMID:12446380
title: TGFbeta-Smad signalling in postoperative human lens epithelial cells.
findings: []
- id: PMID:12650946
title: Identification of three novel Smad binding proteins involved in cell polarity.
findings: []
- id: PMID:12686552
title: Features of a Smad3 MH1-DNA complex. Roles of water and zinc in DNA binding.
findings: []
- id: PMID:12857746
title: Direct interaction of Ski with either Smad3 or Smad4 is necessary and sufficient for Ski-mediated repression of transforming
growth factor-beta signaling.
findings: []
- id: PMID:12874272
title: Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic
protein-induced transcriptional activation.
findings: []
- id: PMID:12902338
title: Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta
action.
findings: []
- id: PMID:14525983
title: DACH1 inhibits transforming growth factor-beta signaling through binding Smad4.
findings: []
- id: PMID:14555988
title: Differential regulation of TGF-beta signaling through Smad2, Smad3 and Smad4.
findings: []
- id: PMID:14612439
title: A novel E1A-like inhibitor of differentiation (EID) family member, EID-2, suppresses transforming growth factor (TGF)-beta
signaling by blocking TGF-beta-induced formation of Smad3-Smad4 complexes.
findings: []
- id: PMID:15051726
title: Atrophin-1-interacting protein 4/human Itch is a ubiquitin E3 ligase for human enhancer of filamentation 1 in transforming
growth factor-beta signaling pathways.
findings: []
- id: PMID:15084259
title: Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation.
findings: []
- id: PMID:15107418
title: Activin receptor-like kinase-7 induces apoptosis through activation of MAPKs in a Smad3-dependent mechanism in hepatoma
cells.
findings: []
- id: PMID:15150278
title: Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells.
findings: []
- id: PMID:15231748
title: Functional proteomics mapping of a human signaling pathway.
findings: []
- id: PMID:15334054
title: Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-beta/Smad3-mediated transcriptional
activation.
findings: []
- id: PMID:15350224
title: Structural basis of heteromeric smad protein assembly in TGF-beta signaling.
findings: []
- id: PMID:15527767
title: 'Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits
its transcriptional activity.'
findings: []
- id: PMID:15588252
title: The Smad3 linker region contains a transcriptional activation domain.
findings: []
- id: PMID:15647271
title: The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling
by the transforming growth factor-{beta} superfamily of cytokines.
findings: []
- id: PMID:15781469
title: CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3
through ubiquitin-mediated degradation.
findings: []
- id: PMID:15799969
title: Nuclear targeting of transforming growth factor-beta-activated Smad complexes.
findings: []
- id: PMID:15897867
title: Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP.
findings: []
- id: PMID:16007207
title: Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3
and inhibit the TGF-beta pathway.
findings: []
- id: PMID:16200078
title: Cloning and functional characterization of a new Ski homolog, Fussel-18, specifically expressed in neuronal tissues.
findings: []
- id: PMID:16751101
title: PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.
findings: []
- id: PMID:16777850
title: The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity.
findings: []
- id: PMID:16886151
title: Association of polymorphisms of IGF1R and genes in the transforming growth factor- beta /bone morphogenetic protein
pathway with bacteremia in sickle cell anemia.
findings: []
- id: PMID:17099224
title: Potentiation of Smad-mediated transcriptional activation by the RNA-binding protein RBPMS.
findings: []
- id: PMID:17251190
title: The MH1 domain of Smad3 interacts with Pax6 and represses autoregulation of the Pax6 P1 promoter.
findings: []
- id: PMID:17292623
title: Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling.
findings: []
- id: PMID:17469184
title: Involvement of the constitutive complex formation of c-Ski/SnoN with Smads in the impaired negative feedback regulation
of transforming growth factor beta signaling in scleroderma fibroblasts.
findings: []
- id: PMID:17785517
title: Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads.
findings: []
- id: PMID:18505915
title: Transforming growth factor-beta1, transforming growth factor-beta2, and transforming growth factor-beta3 enhance
ovarian cancer metastatic potential by inducing a Smad3-dependent epithelial-to-mesenchymal transition.
findings: []
- id: PMID:18548003
title: SMAD proteins control DROSHA-mediated microRNA maturation.
findings: []
- id: PMID:18568018
title: TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal.
findings: []
- id: PMID:18729074
title: Identification of novel Smad2 and Smad3 associated proteins in response to TGF-beta1.
findings: []
- id: PMID:18794808
title: Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-beta signaling.
findings: []
- id: PMID:18832382
title: HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition.
findings: []
- id: PMID:19018011
title: 'Holding their own: the noncanonical roles of Smad proteins.'
findings: []
- id: PMID:19032343
title: Ski co-repressor complexes maintain the basal repressed state of the TGF-beta target gene, SMAD7, via HDAC3 and PRMT5.
findings: []
- id: PMID:19049980
title: SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells.
findings: []
- id: PMID:19122240
title: Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins.
findings: []
- id: PMID:19135894
title: FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination.
findings: []
- id: PMID:19289081
title: Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling.
findings: []
- id: PMID:19816956
title: MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells
derived from human adipose tissue.
findings: []
- id: PMID:20061380
title: MTMR4 attenuates transforming growth factor beta (TGFbeta) signaling by dephosphorylating R-Smads in endosomes.
findings: []
- id: PMID:20129061
title: TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta
signaling.
findings: []
- id: PMID:20211142
title: An atlas of combinatorial transcriptional regulation in mouse and man.
findings: []
- id: PMID:20935647
title: IL-37 is a fundamental inhibitor of innate immunity.
findings: []
- id: PMID:21145499
title: The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-Ξ²-SMAD pathway.
findings: []
- id: PMID:21258410
title: Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially
modulates TGFΞ² signalling and EMT.
findings: []
- id: PMID:21297662
title: Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-Ξ² cytostatic program and blocks
the antiproliferative effect of TGF-Ξ².
findings: []
- id: PMID:21307346
title: Response gene to complement 32 interacts with Smad3 to promote epithelial-mesenchymal transition of human renal tubular
cells.
findings: []
- id: PMID:21532621
title: Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription
in ovarian cancer cells.
findings: []
- id: PMID:21597466
title: Antagonistic regulation of EMT by TIF1Ξ³ and Smad4 in mammary epithelial cells.
findings: []
- id: PMID:21828274
title: HEB and E2A function as SMAD/FOXH1 cofactors.
findings: []
- id: PMID:21947082
title: USP15 is a deubiquitylating enzyme for receptor-activated SMADs.
findings: []
- id: PMID:21988832
title: Toward an understanding of the protein interaction network of the human liver.
findings: []
- id: PMID:22045334
title: Ablation of Smurf2 reveals an inhibition in TGF-Ξ² signalling through multiple mono-ubiquitination of Smad3.
findings: []
- id: PMID:22155034
title: Bone morphogenetic protein-3b (BMP-3b) inhibits osteoblast differentiation via Smad2/3 pathway by counteracting Smad1/5/8
signaling.
findings: []
- id: PMID:22442258
title: Intercellular variation in signaling through the TGF-Ξ² pathway and its relation to cell density and cell cycle phase.
findings: []
- id: PMID:22538441
title: CSMD1 exhibits antitumor activity in A375 melanoma cells through activation of the Smad pathway.
findings: []
- id: PMID:23723426
title: Kindlin-2 mediates activation of TGF-Ξ²/Smad signaling and renal fibrosis.
findings: []
- id: PMID:24378993
title: Crosstalk between TGF-Ξ²/Smad3 and BMP/BMPR2 signaling pathways via miR-17-92 cluster in carotid artery restenosis.
findings: []
- id: PMID:24613385
title: Hsp70 and Hsp90 oppositely regulate TGF-Ξ² signaling through CHIP/Stub1.
findings: []
- id: PMID:24627487
title: C18 ORF1, a novel negative regulator of transforming growth factor-Ξ² signaling.
findings: []
- id: PMID:24964035
title: Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease.
findings: []
- id: PMID:25060702
title: A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent gene expression.
findings: []
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
- id: PMID:25502805
title: A massively parallel pipeline to clone DNA variants and examine molecular phenotypes of human disease mutations.
findings: []
- id: PMID:25556234
title: New host factors important for respiratory syncytial virus (RSV) replication revealed by a novel microfluidics screen
for interactors of matrix (M) protein.
findings: []
- id: PMID:25605017
title: Reduction of miR-29c enhances pancreatic cancer cell migration and stem cell-like phenotype.
findings: []
- id: PMID:25609649
title: Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
findings: []
- id: PMID:25670079
title: 14-3-3ΞΆ turns TGF-Ξ²'s function from tumor suppressor to metastasis promoter in breast cancer by contextual changes
of Smad partners from p53 to Gli2.
findings: []
- id: PMID:25893292
title: Syntenin regulates TGF-Ξ²1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated
TGF-Ξ² type I receptor internalization.
findings: []
- id: PMID:25910212
title: Widespread macromolecular interaction perturbations in human genetic disorders.
findings: []
- id: PMID:26311719
title: MicroRNA-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension.
findings: []
- id: PMID:26680585
title: ShcA Protects against Epithelial-Mesenchymal Transition through Compartmentalized Inhibition of TGF-Ξ²-Induced Smad
Activation.
findings: []
- id: PMID:27038547
title: MiRNA-199a-5p influences pulmonary artery hypertension via downregulating Smad3.
findings: []
- id: PMID:27060871
title: Suppression of innate inflammation and immunity by interleukin-37.
findings: []
- id: PMID:27107012
title: Pooled-matrix protein interaction screens using Barcode Fusion Genetics.
findings: []
- id: PMID:28467929
title: PPARΞ³ Links BMP2 and TGFΞ²1 Pathways in Vascular Smooth Muscle Cells, Regulating Cell Proliferation and Glucose Metabolism.
findings: []
- id: PMID:28471448
title: MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis.
findings: []
- id: PMID:29789615
title: IL-37 isoform D downregulates pro-inflammatory cytokines expression in a Smad3-dependent manner.
findings: []
- id: PMID:29892012
title: An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.
findings: []
- id: PMID:29899023
title: NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension.
findings: []
- id: PMID:29997244
title: 'LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein
interactions in mammalian cells.'
findings: []
- id: PMID:30729664
title: Novel role of the clustered miR-23b-3p and miR-27b-3p in enhanced expression of fibrosis-associated genes by targeting
TGFBR3 in atrial fibroblasts.
findings: []
- id: PMID:31023188
title: LRP1 Deficiency in Vascular SMC Leads to Pulmonary Arterial Hypertension That Is Reversed by PPARΞ³ Activation.
findings: []
- id: PMID:31515488
title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
findings: []
- id: PMID:31582430
title: Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-Ξ² signaling.
findings: []
- id: PMID:32141990
title: miR-4286/TGF-Ξ²1/Smad3-Negative Feedback Loop Ameliorated Vascular Endothelial Cell Damage by Attenuating Apoptosis
and Inflammatory Response.
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation
in Affected Brains.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
findings: []
- id: PMID:34432647
title: GDF-8 stimulates trophoblast cell invasion by inducing ALK5-SMAD2/3-mediated MMP2 expression.
findings: []
- id: PMID:35359452
title: The Interplay Between TGF-Ξ² Signaling and Cell Metabolism.
findings: []
- id: PMID:35512704
title: Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
findings: []
- id: PMID:39243984
title: Gain-of-function variants in SMAD4 compromise respiratory epithelial function.
findings: []
- id: PMID:8774881
title: Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.
findings: []
- id: PMID:9111321
title: Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and
Smad4/DPC4.
findings: []
- id: PMID:9311995
title: TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4.
findings: []
- id: PMID:9732876
title: Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription.
findings: []
- id: PMID:9865696
title: SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor.
findings: []
- id: PMID:9892009
title: Roles of pathway-specific and inhibitory Smads in activin receptor signaling.
findings: []
- id: Reactome:R-HSA-1535903
title: Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXO3 binds FoxO3a-binding elements
findings: []
- id: Reactome:R-HSA-1549526
title: Phosphorylation of SMAD2,3 by Activin:Activin Receptor
findings: []
- id: Reactome:R-HSA-170835
title: An anchoring protein, ZFYVE9 (SARA), recruits SMAD2/3
findings: []
- id: Reactome:R-HSA-170847
title: Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4
findings: []
- id: Reactome:R-HSA-170850
title: Phosphorylated SMAD2/3 dissociates from TGFBR
findings: []
- id: Reactome:R-HSA-170868
title: Activated type I receptor phosphorylates SMAD2/3 directly
findings: []
- id: Reactome:R-HSA-173481
title: SKI/SKIL binds SMAD complex, suppressing TGF-beta signaling
findings: []
- id: Reactome:R-HSA-173488
title: The SMAD2/3:SMAD4 complex transfers to the nucleus
findings: []
- id: Reactome:R-HSA-173545
title: Ubiquitin-dependent degradation of the SMAD complex terminates TGF-beta signaling
findings: []
- id: Reactome:R-HSA-2031355
title: WWTR1 binds SMAD2/3:SMAD4 heterotrimer
findings: []
- id: Reactome:R-HSA-209055
title: PPM1A dephosphorylates nuclear SMAD2/3
findings: []
- id: Reactome:R-HSA-2106579
title: WWTR1:SMAD translocates to the nucleus
findings: []
- id: Reactome:R-HSA-2127257
title: SMAD2/3:SMAD4 heterotrimer forms a complex with RBL1, E2F4/5 and DP1/2
findings: []
- id: Reactome:R-HSA-2176475
title: Phosphorylation of SMAD2 and SMAD3 linker regions by CDK8 or CDK9
findings: []
- id: Reactome:R-HSA-2176491
title: NEDD4L binds phosphorylated linker region of SMAD2/3
findings: []
- id: Reactome:R-HSA-2176502
title: NEDD4L ubiquitinates SMAD2/3
findings: []
- id: Reactome:R-HSA-2176503
title: Degradation of SMAD2/3:SMAD4 complex
findings: []
- id: Reactome:R-HSA-2179274
title: SMURF2 binds SMAD3 phosphorylated in the linker region
findings: []
- id: Reactome:R-HSA-2179276
title: SMURF2 monoubiquitinates SMAD3
findings: []
- id: Reactome:R-HSA-2186607
title: TGIF recruits HDAC1 to SMAD2/3:SMAD4 heterotrimer
findings: []
- id: Reactome:R-HSA-2186643
title: MEN1 binds SMAD2/3:SMAD4 heterotrimer
findings: []
- id: Reactome:R-HSA-2187309
title: SMAD2/3:SMAD4 heterotrimer binds SP1
findings: []
- id: Reactome:R-HSA-2187325
title: PARP1 ADP-ribosylates SMAD3 and SMAD4
findings: []
- id: Reactome:R-HSA-2187330
title: PARP1 binds SMAD2/3:SMAD4 heterotrimer
findings: []
- id: Reactome:R-HSA-2187355
title: PMEPA1 sequesters phosphorylated SMAD2/3
findings: []
- id: Reactome:R-HSA-2187358
title: PMEPA1 sequesters unphosphorylated SMAD2/3
findings: []
- id: Reactome:R-HSA-2187368
title: STUB1 (CHIP) ubiquitinates SMAD3
findings: []
- id: Reactome:R-HSA-2187375
title: SMAD3 binds STUB1 (CHIP)
findings: []
- id: Reactome:R-HSA-2187382
title: Degradation of ubiquitinated SMAD3
findings: []
- id: Reactome:R-HSA-2187388
title: PPM1A protein phosphatase binds phosphorylated SMAD2/3
findings: []
- id: Reactome:R-HSA-2187395
title: Dephosphorylated SMAD2/3 translocates to the cytosol
findings: []
- id: Reactome:R-HSA-2187401
title: MTMR4 dephosphorylates SMAD2/3
findings: []
- id: Reactome:R-HSA-2187405
title: MTMR4 binds phosphorylated SMAD2/3
findings: []
- id: Reactome:R-HSA-3311014
title: SMAD4 MH2 Domain Mutants do not bind phosphorylated SMAD2 and SMAD3
findings: []
- id: Reactome:R-HSA-3315483
title: Phosphorylated SMAD2/3 MH2 Domain Mutants do not bind SMAD4
findings: []
- id: Reactome:R-HSA-3656523
title: An anchoring protein ZFYVE9 (SARA) does not recruit SMAD2/3 to TGFB1:TGFBR2:p-TGFBR1 KD Mutants
findings: []
- id: Reactome:R-HSA-6781764
title: USP15 deubiquitinates SMAD1,SMAD2,SMAD3, SMAD7:SMURF,KEAP1
findings: []
- id: Reactome:R-HSA-870449
title: TRIM33 monoubiquitinates SMAD4
findings: []
- id: Reactome:R-HSA-870538
title: TRIM33 (Ectodermin) binds SMAD heterotrimer in the nucleus
findings: []
- id: Reactome:R-HSA-8878143
title: RUNX3 binds SMAD3 and SMAD4
findings: []
- id: Reactome:R-HSA-8878178
title: The complex of RUNX3, SMAD3 and SMAD4 binds the CDKN1A gene promoter
findings: []
- id: Reactome:R-HSA-8952226
title: RUNX3 binds the BCL2L11 (BIM) gene
findings: []
- id: Reactome:R-HSA-9008692
title: IL37(?-218) binds SMAD3
findings: []
- id: Reactome:R-HSA-9008928
title: IL37(?-218):p-S423,S425-SMAD3 translocates to the nucleus
findings: []
- id: Reactome:R-HSA-9009910
title: IL37(?-218) binds p-S423,S425-SMAD3
findings: []
- id: Reactome:R-HSA-9617996
title: FOXO1,FOXO3,FOXO4 bind p-2S-SMAD2/3:SMAD4
findings: []
- id: Reactome:R-HSA-9618004
title: FOXO:SMAD complex binds CDKN1A gene promoter
findings: []
- id: Reactome:R-HSA-9618021
title: FOXG1 binds FOXO:SMAD complexes
findings: []
- id: Reactome:R-HSA-9727922
title: SARS-CoV-1 SUMO1-K62-p-S177-N dimer binds to SMAD3
findings: []
- id: Reactome:R-HSA-9731111
title: MAPK1 and MAPK3 phosphorylate SMAD2 and SMAD3
findings: []
- id: Reactome:R-HSA-9733207
title: p-2S-SMAD3:p-2S-SMAD3:SMAD4 forms a complex with SP1 and EP300 at the COL1A2 gene promoter
findings: []
- id: Reactome:R-HSA-9733247
title: YBX1 binds COL1A2 gene promoter
findings: []
- id: Reactome:R-HSA-9736959
title: WWTR1:p-2S-SMAD2,3:SMAD4 binds SERPINE1 gene promoter
findings: []
- id: Reactome:R-HSA-9736970
title: WWTR1:p-2S-SMAD2,3:SMAD4 binds SMAD7 gene promoter
findings: []
- id: Reactome:R-HSA-9736979
title: p-2S-SMAD2,3:SMAD4:SP1 binds CDKN2B gene promoter
findings: []
- id: Reactome:R-HSA-9736984
title: p-2S-SMAD2,3:SMAD4:RBL1:E2F4,5:DP1,2 binds MYC gene promoter
findings: []
- id: Reactome:R-HSA-9736992
title: p-2S-SMAD2,3:SMAD4 binds JUNB gene promoter
findings: []
- id: Reactome:R-HSA-9737710
title: SARS-CoV-1 N binds SMAD3 and EP300 at the SERPINE1 gene promoter
findings: []
- id: Reactome:R-HSA-9823952
title: EOMES, SMAD2,3, and GATA6 bind the CXCR4 gene
findings: []
- id: Reactome:R-HSA-9823959
title: SMAD2,3 and GATA6-AS1 lncRNA bind the GATA6 gene
findings: []
- id: Reactome:R-NUL-2186736
title: Rnf111 binds SKI/SKIL in complex with SMAD2/3:SMAD4 upon TGF-beta stimulation
findings: []
- id: Reactome:R-NUL-2186755
title: Ubiquitination of SKI/SKIL by Rnf111
findings: []
- id: Reactome:R-NUL-9625758
title: FOXO1,FOXO3 and SMAD3 bind Trim63 gene promoter
findings: []
core_functions:
- description: 'SMAD3 functions as a sequence-specific DNA-binding transcription factor for RNA polymerase II. The MH1 domain
directly binds SMAD binding elements (SBE: GTCT/AGAC) and CAGA-box motifs, and cooperates with coactivators (p300/CBP)
or corepressors (Ski/SnoN/TGIF) to regulate target gene transcription.'
molecular_function:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
directly_involved_in:
- id: GO:0045893
label: positive regulation of DNA-templated transcription
- id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
- id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
locations:
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: PMID:9732876
supporting_text: Smad3 interacts directly with the TRE and that Smad3 and Smad4 can activate TGF-beta-inducible transcription
from the TRE in the absence of c-Jun and c-Fos.
- reference_id: PMID:8774881
supporting_text: hMAD-3 and -4 synergized to induce strong ligand-independent TGF-beta-like responses.
- description: SMAD3 binds the activated TGF-beta type I receptor (ALK5/TGFBR1) as the principal intracellular signal transducer.
Upon receptor binding and C-terminal SSXS phosphorylation, SMAD3 forms heteromeric complexes with SMAD4 and translocates
to the nucleus.
molecular_function:
id: GO:0070410
label: co-SMAD binding
directly_involved_in:
- id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
- id: GO:0060395
label: SMAD protein signal transduction
locations:
- id: GO:0005737
label: cytoplasm
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: PMID:9311995
supporting_text: Smad2 and Smad3 interacted with the kinase-deficient TGF-beta type I receptor (TbetaR)-I after it was
phosphorylated by TbetaR-II kinase. TGF-beta1 induced phosphorylation of Smad2 and Smad3 in Mv1Lu mink lung epithelial
cells.
- description: SMAD3 binds to cis-regulatory DNA sequences including SMAD binding elements (SBE) and TPA-responsive elements
(TRE/AP-1 sites), acting as a direct DNA-binding component of the TGF-beta transcriptional response.
molecular_function:
id: GO:0000976
label: transcription cis-regulatory region binding
directly_involved_in:
- id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
locations:
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: PMID:9732876
supporting_text: 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.