| + |
SMAD3/SMAD4 | up-regulates quantity by expression 
transcriptional regulation
|
JUNB |
0.555 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-59476 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 9694870 |
Here we report the identification of Smad Binding Elements (SBEs) composed of the sequence CAGACA in the promoter of the JunB gene, an immediate early gene that is potently induced by TGF-beta, activin, and bone morphogenetic protein (BMP) 2. Two JunB SBEs are arranged as an inverted repeat that is transactivated in response to Smad3 and Smad4 co-overexpression and shows inducible binding of a Smad3- and Smad4-containing complex in nuclear extracts from TGF-beta-treated cells. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
SMAD3/SMAD4 | up-regulates quantity by expression
transcriptional regulation
|
BCL2L11 |
0.475 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-260425 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 17960585 |
Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, Fibrosis, SARS-CoV FIBROSIS |
| + |
NUP214 | up-regulates activity 
relocalization
|
SMAD3/SMAD4 |
0.532 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-217719 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12917407 |
We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
TGFb | up-regulates quantity by expression
transcriptional regulation
|
SMAD3/SMAD4 |
0.616 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-260428 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 30017632 |
Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, Fibrosis, Hepatocellular Tumor, Multiple sclerosis, Pancreatic ductal adenocarcinoma (PDA), SARS-CoV FIBROSIS, TGFb in cancer |
| + |
SMAD3/SMAD4 | up-regulates
|
Fibrosis |
0.7 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-260441 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 30017632 |
Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes |
|
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-254375 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 24877152 |
Conversely, a reduced amount of IGF-1R diminished the levels of P-AKT, allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFβ1 signaling pathway and fibrosis |
|
| Publications: |
2 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, Fibrosis, SARS-CoV FIBROSIS, TGF-beta Signaling |
| + |
SMAD3/SMAD4 | up-regulates activity
binding
|
JUN |
0.701 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-229545 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 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 |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | TGF-beta Signaling |
| + |
PIAS4 | down-regulates activity 
binding
|
SMAD3/SMAD4 |
0.583 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-217731 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12904571 |
Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
SMAD3/SMAD4 | up-regulates activity
binding
|
AP1 |
0.628 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-256181 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 22926518 |
The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. |
|
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-253332 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 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 |
|
| Publications: |
2 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, Hepatocellular Tumor, Multiple sclerosis, Pancreatic ductal adenocarcinoma (PDA), TGF-beta Signaling, TGFb in cancer |
| + |
SMAD3/SMAD4 | up-regulates activity
binding
|
ATF2 |
0.577 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-65583 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 10085140 |
Here we report that the transcription factor atf-2 (also called cre-bp1) is bound by a hetero-oligomer of smad3 and smad4 upon tgf-beta stimulation. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, TGF-beta Signaling |
| + |
SMAD3/SMAD4 | up-regulates quantity by expression
transcriptional regulation
|
NANOG |
0.433 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-242055 |
|
|
Homo sapiens |
Embryonic Stem Cell |
| pmid |
sentence |
| 19279133 |
Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs. |
|
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-242052 |
|
|
Homo sapiens |
Esophageal Squamous Cell Carcinoma Cell |
| pmid |
sentence |
| 18682241 |
We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity. |
|
| Publications: |
2 |
Organism: |
Homo Sapiens |
| + |
SMAD3/SMAD4 | down-regulates activity
binding
|
MYOD1 |
0.623 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-254986 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12244043 |
Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
SMAD4 | form complex 
binding
|
SMAD3/SMAD4 |
0.691 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-229560 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 9843571 |
TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | Hepatocellular Tumor, Pancreatic ductal adenocarcinoma (PDA), TGF-beta Signaling, TGFb in cancer |
| + |
SMAD3/SMAD4 | down-regulates activity
transcriptional regulation, binding
|
CEBPB |
0.556 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-253538 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 17139329 |
Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter |
|
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-97117 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12524424 |
C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. |
|
| Publications: |
2 |
Organism: |
Homo Sapiens |
| + |
SMAD3/SMAD4 | down-regulates activity 
transcriptional regulation
|
MYOD1 |
0.623 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-254987 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12244043 |
Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
SMAD3 | form complex
binding
|
SMAD3/SMAD4 |
0.691 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-229557 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 9843571 |
TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, Fibrosis, Hepatocellular Tumor, Multiple sclerosis, Pancreatic ductal adenocarcinoma (PDA), SARS-CoV FIBROSIS, TGF-beta Signaling, TGFb in cancer |
| + |
N | down-regulates quantity
binding
|
SMAD3/SMAD4 |
0.2 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-260427 |
|
|
Homo sapiens |
Lung |
| pmid |
sentence |
| 18055455 |
In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, SARS-CoV FIBROSIS |
| + |
SMAD3/SMAD4 | down-regulates
binding
|
CEBPD |
0.328 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-97120 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12524424 |
C/ebpbeta and c/ebpdelta were found to physically interact with smad3 and smad4, and smad3 cooperated with smad4 and tgf-beta signaling to repress the transcriptional activity of c/ebps. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
SKIL | down-regulates activity
binding
|
SMAD3/SMAD4 |
0.834 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-253303 |
|
|
Homo sapiens |
Melanoma Cell |
| pmid |
sentence |
| 12793438 |
The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | TGF-beta Signaling |
| + |
VPS39 | down-regulates quantity
binding
|
SMAD3/SMAD4 |
0.324 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-261378 |
|
|
Chlorocebus aethiops |
|
| pmid |
sentence |
| 12941698 |
Overexpression of TLP blocks TGF-β-induced formation of Smad3/4 complexes while it does not alter Smad2/4 complex levels. |
|
| Publications: |
1 |
Organism: |
Chlorocebus Aethiops |
| + |
SMAD3/SMAD4 | down-regulates activity
binding
|
CEBPA |
0.376 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-250571 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12524424 |
C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
SMAD3/SMAD4 | up-regulates quantity by expression
transcriptional regulation
|
CDKN2B |
0.586 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-256286 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 11013220 |
Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | Pancreatic ductal adenocarcinoma (PDA), TGF-beta Signaling, TGFb in cancer |
| + |
SMAD3/SMAD4 | up-regulates
|
M2_polarization |
0.7 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-249551 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 22703233 |
Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products. |
|
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-253587 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 27418133 |
The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines |
|
| Publications: |
2 |
Organism: |
Homo Sapiens |
| Pathways: | Multiple sclerosis |
| + |
SMAD3/SMAD4 | up-regulates
transcriptional regulation
|
LEF1 |
0.606 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-217169 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 10890911 |
Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | Hepatocellular Tumor |
| + |
SMAD3/SMAD4 | down-regulates quantity by repression
transcriptional regulation
|
MYC |
0.649 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-256290 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 11689553 |
To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | Hepatocellular Tumor |
| + |
EID2 | down-regulates activity
binding
|
SMAD3/SMAD4 |
0.41 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-119174 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 14612439 |
Stable expression of eid-2 in the tgf-beta1-responsive cell line inhibits endogenous smad3-smad4 complex formation and tgf-beta1-induced expression of p21 and p15. These results suggest that eid-2 may function as an endogenous suppressor of tgf-beta signaling. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
SKI | down-regulates activity
binding
|
SMAD3/SMAD4 |
0.761 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-253301 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12793438 |
The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | TGF-beta Signaling |
| + |
SMAD3/SMAD4 | down-regulates activity
|
JUN |
0.701 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-249557 |
|
|
Homo sapiens |
Macrophage |
| pmid |
sentence |
| 10973958 |
NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | TGF-beta Signaling |
| + |
SMAD3/SMAD4 | up-regulates quantity by expression
transcriptional regulation
|
SERPINE1 |
0.574 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-57776 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 9606191 |
Here we report the identification of smad3/smad4 binding sequences, termed caga boxes, within the promoter of the human pai-1 gene. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, Fibrosis, SARS-CoV FIBROSIS |
| + |
SMAD3/SMAD4 | down-regulates activity
|
PPARG |
0.423 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-253537 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 17139329 |
Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| + |
SMAD3/SMAD4 | down-regulates activity
|
NfKb-p65/p50 |
0.34 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-249554 |
|
|
Homo sapiens |
Macrophage |
| pmid |
sentence |
| 10973958 |
NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters. |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
| Pathways: | COVID-19 Causal Network, Fibrosis, Multiple sclerosis, Pancreatic ductal adenocarcinoma (PDA), SARS-CoV FIBROSIS |
| + |
SMAD3/SMAD4 | down-regulates
|
Skeletal_muscle_differentiation |
0.7 |
| Identifier |
Residue |
Sequence |
Organism |
Cell Line |
| SIGNOR-254989 |
|
|
Homo sapiens |
|
| pmid |
sentence |
| 12244043 |
Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes |
|
| Publications: |
1 |
Organism: |
Homo Sapiens |
3.0
SMAD3/SMAD4
CPX-3252