Identifiers
SMAD family member 3
HUGO:SMAD3 hgnc_id:HGNC:6769 HGNC:6769 ENTREZ:4088 UNIPROT:P84022
HUGO:SMAD3, HGNC:6769, ENTREZ:4088, UNIPROT:P84022, GENECARDS:GC15P067358
HUGO:SMAD3
"MAD mothers against decapentaplegic homolog 3 (Drosophila)" MADH3 "SMAD mothers against DPP homolog 3 (Drosophila)"
HUGO:SMAD3 HGNC:6769 ENTREZ:4088 UNIPROT:P84022
Maps_Modules
HMC:TUMOR_PROMOTING_INFLAMMATION
HMC:ACTIVATING_INVASION_AND_METASTASIS
Cancer Associated Fibroblasts / GROWTH_FACTORS_SIGNALING_PATHWAYS
EMT Senescence / EMT_REGULATORS
Innate Immunity / IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS
HMC:EVADING_GROWTH_SUPPRESSORS
Survival / MAPK
References
CASCADE:TGFB
PMID:11792802, PMID:12809600
The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation.
PMID:11279127
Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-??-induced ECM Promoter Activation in fibroblasts
COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1
PMID:12702545, PMID:8515656
Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression.
Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment
PMID:16179589
NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts.
On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated.
Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation
MACROPHAGE
NATURAL_KILLER
PMID:18768831
TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells.
SMAD3 downstream of TGFB inhibits expression TBX21 (T-BET). TBX21 is involeved in IFNG gene activation.
PMID:16713975
TGF-?? signaling could target IFNG gene expression via TBX21 (TBET) and in a SMAD-dependent fashion that is independent of T-BET.
SMAD3 can directly interact with IFNG promoter.
PMID:21042762
Inhibition of TGF-?? signalinginduced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner via SMADs.
PMID:22331441
Smad2/3 inhibited IFN-?? production by suppressing IRF3 transcriptional activity.
Smad2/3 somehow suppresses IRF3 phosphorylation in macrophages
Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-??-STAT1 pathway
TGF-?? exerts its biological effects by binding to a cell surface receptor complex composed of type I (TbRI) and type II (TbRII) receptor serine/threonine kinases. Upon ligand binding TbRII phosphorylates and activates TbRI which subsequently phosphorylates the cytoplasmic Smad2 and Smad3 proteins. Phosphorylated Smad proteins form stable complexes with a common partner Smad4. The activated Smad2/4 and Smad3/4 complexes translocate into the nucleus where the Smad oligomers induce transcriptional activation (or inhibition) of specific target genes.
PMID:21614932
References
em_emtc_emtc_re223( EMT Senescence ):
PMID:9865696
Phosphorylation of Smad2 induces dissociation from SARA
with concomitant formation of Smad2/ Smad4 complexes
and nuclear translocation.
em_emtc_emtc_re229( EMT Senescence ):
PMID:11792802
Following phosphorylation of R-Smads by TGFBR1, Smad oligomerization is thought to occur.
PMID:9670020
Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1
This oligomerization does not require Smad4.
em_emtc_emtc_re1263( EMT Senescence ):
Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2/ Smad4 complexes and nuclear translocation.
em_emtc_emtc_re1276( EMT Senescence ):
PMID:10197981
PMID:12193595
PMID:16156666
Erk kinases phosphorylate Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain.
These sites are separate from the TGFB receptor phosphorylation sites that activate Smad nuclear translocation.
Feedback loop: TGFB activates Ras/Raf/Mek/Erk signaling (PMID:17673906) and Erk reduces TGFB/Smads transcriptional activity.
PMID:15241418
Feedback loop
CDK phosphorylation of Smad3 on Thr8/Thr179/Ser213 inhibits its transcriptional activity and antiproliferative function.
Because cancer cells often contain high levels of CDK activity, diminishing Smad3 activity by CDK phosphorylation may contribute to tumorigenesis and TGFB- resistance in
cancers.
Maps_Modules
HMC:ACTIVATING_INVASION_AND_METASTASIS
EMT Senescence / EMT_REGULATORS
EMT Senescence / ECM
References
PMID:9670020
Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1
This oligomerization does not require Smad4.
em_emtc_emtc_re229( EMT Senescence ):
PMID:11792802
Following phosphorylation of R-Smads by TGFBR1, Smad oligomerization is thought to occur.
em_emtc_emtc_re231( EMT Senescence ):
PMID:11224571
Phosphorylated Smad3 recruits Smad4 to form a heterotrimer
containing 2 Smad3 and 1 Smad4.
References
em_emtc_emtc_re1276( EMT Senescence ):
PMID:10197981
PMID:12193595
PMID:16156666
Erk kinases phosphorylate Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain.
These sites are separate from the TGFB receptor phosphorylation sites that activate Smad nuclear translocation.
Feedback loop: TGFB activates Ras/Raf/Mek/Erk signaling (PMID:17673906) and Erk reduces TGFB/Smads transcriptional activity.
PMID:15241418
Feedback loop
CDK phosphorylation of Smad3 on Thr8/Thr179/Ser213 inhibits its transcriptional activity and antiproliferative function.
Because cancer cells often contain high levels of CDK activity, diminishing Smad3 activity by CDK phosphorylation may contribute to tumorigenesis and TGFB- resistance in
cancers.
References
su_mpk1_mpk1_re252( Survival ):
TGF-?? exerts its biological effects by binding to a cell surface receptor complex composed of type I (TbRI) and type II (TbRII) receptor serine/threonine kinases. Upon ligand binding TbRII phosphorylates and activates TbRI which subsequently phosphorylates the cytoplasmic Smad2 and Smad3 proteins. Phosphorylated Smad proteins form stable complexes with a common partner Smad4. The activated Smad2/4 and Smad3/4 complexes translocate into the nucleus where the Smad oligomers induce transcriptional activation (or inhibition) of specific target genes.
PMID:21614932
→ SMAD3|pho@Cytosol
+ SMAD4@Cytosol → SMAD3|pho:SMAD4@Cytosol
→ SMAD3@Cytosol
+ SMAD7@Cytosol → SMAD3:SMAD7@Cytosol
+ SMAD2|S467_pho|S465_pho@Cytosol → SMAD2|S467_pho|S465_pho:SMAD3|S423_pho|S425_pho@Cytosol
→ SMAD3|S423_pho|S425_pho|hm2|active@Cytosol
→ SMAD2|S467_pho|S465_pho:SMAD3|S423_pho|S425_pho@Cytosol
→ SMAD3|T179_pho|S204_pho|S208_pho|S213_pho|S423_pho|S425_pho@Cytosol
→ SMAD3@Cytosol
+ SARA*@Early Endosome → SARA*:SMAD3@Early Endosome
+ ATP@Cytosol → SARA*:SMAD3|S423_pho|S425_pho@Early Endosome + ADP@Cytosol
→ SARA*@Early Endosome + SMAD3|S423_pho|S425_pho@Cytosol
→ SMAD3|S423_pho|S425_pho|hm2|active@Cytosol
+ SMAD3|S423_pho|S425_pho|hm2|active@Cytosol → em_emtc_emtc_s562
(SMAD3|S423_pho|S425_pho|hm2:SMAD4)|active@Nucleus
+ (SMAD3|S423_pho|S425_pho|hm2:SMAD4)|active@Nucleus → (SMAD3|S423_pho|S425_pho|hm2:SMAD4:SNAI1)|active@Nucleus
+ (SMAD2|S467_pho|S464_pho|S465_pho:SMAD3|S422_pho|S423_pho|S425_pho:SMAD4:SP1)|active@Nucleus → (MIZ1*:SMAD2|S467_pho|S464_pho|S465_pho:SMAD3|S422_pho|S423_pho|S425_pho:SMAD4:SP1)|active@Nucleus
+ SP1@Nucleus → SMAD3|S423_pho|S425_pho|hm2:SMAD4:SP1@Nucleus
→ SMAD3|pho@INNATE_IMMUNE_CELL_Cytosol
+ SMAD4@INNATE_IMMUNE_CELL_Cytosol → SMAD3|pho:SMAD4@INNATE_IMMUNE_CELL_Cytosol
→ SMAD3@INNATE_IMMUNE_CELL_Cytosol
+ SMAD4@Cytoplasm → su_mpk1_mpk1_s1027
→ rFAP@Cytosol
→ rCollagens*@Cytosol
→ rTIMP1@Cytosol
→ rS100A4@Cytosol
→ rTNC@Cytosol
→ rITGB5@Cytosol
→ SP1@Cytosol
→ ETS1@Cytosol
→ rITGA11@Cytosol
→ rLOX@Cytosol
→ rFGF2@Cytosol
→ rCTGF@Cytosol
→ rGLI1@Cytosol
→ rGLI2@Cytosol
→ rPOSTN@Cytosol
→ rACTA2@Cytosol
→ rHEY1@Nucleus
→ rCAR*@Nucleus
→ rClaudin3*@Nucleus
→ rp15INK4B*@Nucleus
→ rp21CIP1*@Nucleus
→ rE-Cadherin*@Nucleus
→ rCOL1A2@Nucleus
→ rOccludin*@Nucleus
→ rZEB1@Nucleus
→ IL12*@default
→ rTBX21@INNATE_IMMUNE_CELL_Cytosol
→ rARG1@INNATE_IMMUNE_CELL_Cytosol
→ rNOS2@INNATE_IMMUNE_CELL_Cytosol
→ rIFNG@INNATE_IMMUNE_CELL_Cytosol
→ IRF3|pho@INNATE_IMMUNE_CELL_Cytosol