Identifiers
SMAD family member 2
HUGO:SMAD2 hgnc_id:HGNC:6768 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796
HUGO:SMAD2, HGNC:6768, ENTREZ:4087, UNIPROT:Q15796, GENECARDS:GC18M045357
"MAD mothers against decapentaplegic homolog 2 (Drosophila)" MADH2 "SMAD mothers against DPP homolog 2 (Drosophila)"
HUGO:SMAD2 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796
HUGO:SMAD2 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 GENECARDS:SMAD2 REACTOME:405890 KEGG:4087 ATLASONC:SMAD2ID370 WIKI:SMAD2
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
Survival / WNT_CANONICAL
References
CASCADE:TGFB
PMID:15265520 , PMID:11279127
TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts.
For the TGF-?? pathway, the Smad proteins, Smad2 and Smad3, are ligand-responsive
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
PMID:9670020
Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGFBR1
This oligomerization does not require Smad4.
PMID:11074002
Upon TGFB signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export.
After prolonged TGFB signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm
CASCADE:IL12
CASCADE:IL18
PMID:16713975
SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB.
costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript.
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_re218( EMT Senescence ):
PMID:9865696
Phosphorylation of Smad2 induces dissociation from SARA
with concomitant formation of Smad2/ Smad4 complexes
and nuclear translocation.
em_emtc_emtc_re230( 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_re1277( 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.
References
em_emtc_emtc_re230( 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.
References
em_emtc_emtc_re1277( 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.
References
su_mpk1_mpk1_re251( 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
Maps_Modules
HMC:EVADING_GROWTH_SUPPRESSORS
Survival / WNT_CANONICAL
References
s_wca2_re48:( Survival ) part of canonical TGF pathway
s_wca2_re47:( Survival ) PMID:19104148
→ SMAD2|pho@Cytosol
+ SMAD4@Cytosol → SMAD2|pho:SMAD4@Cytosol
+ SMAD7@Cytosol → SMAD2:SMAD7@Cytosol
+ SMAD2|S467_pho|S465_pho@Cytosol → SMAD2|S467_pho|S465_pho:SMAD3|S423_pho|S425_pho@Cytosol
→ SMAD2|S467_pho|S465_pho:SMAD3|S423_pho|S425_pho@Cytosol
→ SMAD2|S467_pho|S465_pho|hm2|active@Cytosol
→ SMAD2|S467_pho|S465_pho|T8_pho@Cytosol
→ SMAD2@Cytosol
+ SARA*@Early Endosome → SARA*:SMAD2@Early Endosome
+ ATP@Cytosol → SARA*:SMAD2|S467_pho|S465_pho@Early Endosome + ADP@Cytosol
→ SMAD2|S467_pho|S465_pho@Cytosol + SARA*@Early Endosome
→ SMAD2|S467_pho|S465_pho|hm2|active@Cytosol
+ (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
→ SMAD2|pho@INNATE_IMMUNE_CELL_Cytosol
+ SMAD4@INNATE_IMMUNE_CELL_Cytosol → SMAD2|pho:SMAD4@INNATE_IMMUNE_CELL_Cytosol
→ SMAD2@INNATE_IMMUNE_CELL_Cytosol
+ SMAD4@Cytoplasm → su_mpk1_mpk1_s1028
→ TCF_LEF transcriptional_br_regulation@Nucleus
→ EMT@Nucleus
+ SMAD2|pho@Nucleus → SMAD2|pho:_beta_-Catenin*|Y654_pho@Nucleus
→ SMAD2|pho@Nucleus
→ rS100A4@Cytosol
→ rITGA11@Cytosol
→ rPOSTN@Cytosol
→ rNOX4@Cytosol
→ rp15INK4B*@Nucleus
→ rp21CIP1*@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