Identifiers
SMAD family member 4
HUGO:SMAD4 hgnc_id:HGNC:6770 HGNC:6770 ENTREZ:4089 UNIPROT:Q13485
HUGO:SMAD4
HUGO:SMAD4, HGNC:6770, ENTREZ:4089, UNIPROT:Q13485, GENECARDS:GC18P048494
"MAD mothers against decapentaplegic homolog 4 (Drosophila)" MADH4 "SMAD mothers against DPP homolog 4 (Drosophila)"
HUGO:SMAD4 HGNC:6770 ENTREZ:4089 UNIPROT:Q13485
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:15265520 , PMID:11279127
TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts
PMID:12702545
Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment
PMID:9389648
Smad4 has the same overall structure as the receptor-regulated SMADs
Smad4 is more divergent and lacks the C-ter phosphorylation motif.
Smad4 is not required for nuclear translocation of Smads 1 or 2
Receptor-activated Smad2 takes Smad4 into the nucleus where they form a complex with FAST-1 that requires these three components to activate transcription.
Smad4 contributes 2 functions:
N-ter-Smad4 promotes binding of the Smad2/Smad4/FAST-1 complex to DNA;
C-ter-Smad4 activates Smad1 or Smad2 to stimulate transcription
PMID:11074002
In the absence of TGFB signaling, Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm
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
MACROPHAGE
NATURAL_KILLER
PMID:16713975
SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB.
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
mo_re72:( motility ) PMID:21084277
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
+ SMAD4@Cytosol → SMAD3|pho:SMAD4@Cytosol
+ SMAD4@Cytosol → SMAD2|pho:SMAD4@Cytosol
→ SMAD4@Cytosol
+ HMGA2@Nucleus → HMGA2:SMAD2_3*:SMAD4@Nucleus
SMAD2_3*:SMAD4@Nucleus
+ ATF3@Nucleus → ATF3:SMAD2_3*:SMAD4@Nucleus
→ SMAD4@Cytosol
SMAD2_3*:SMAD4@Nucleus
+ SMAD3|S423_pho|S425_pho|hm2|active@Cytosol → em_emtc_emtc_s562
+ SMAD2_3*@Cytosol → em_emtc_emtc_s3914
(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_3*:SMAD4@Nucleus → SMAD2_3*:SMAD4:ZEB1@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
+ SMAD4@INNATE_IMMUNE_CELL_Cytosol → SMAD3|pho:SMAD4@INNATE_IMMUNE_CELL_Cytosol
+ SMAD4@INNATE_IMMUNE_CELL_Cytosol → SMAD2|pho:SMAD4@INNATE_IMMUNE_CELL_Cytosol
+ SMAD4|pho|active@Nucleus → SMAD2_3*|pho:SMAD4|pho@Nucleus
+ gSBE promoter*@Nucleus → SBE promoter*:SMAD2_3*|pho:SMAD4|pho@Nucleus
+ SMAD4@Cytoplasm → su_mpk1_mpk1_s1028
+ 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
→ rNOX4@Cytosol
→ rACTA2@Cytosol
→ rSNAI1@Nucleus
→ rID1@Nucleus
→ rATF3@Nucleus
→ rHEY1@Nucleus
→ rSNAI2@Nucleus
→ rCAR*@Nucleus
→ rClaudin3*@Nucleus
→ rp15INK4B*@Nucleus
→ rp21CIP1*@Nucleus
→ rE-Cadherin*@Nucleus
→ rCOL1A2@Nucleus
→ rOccludin*@Nucleus
→ rZEB1@Nucleus
→ rZEB2@Nucleus
→ rTWIST1@Nucleus
→ rTWIST2@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
→ rPTP4A3@Nucleus