SMAD2_3*:SMAD4

Complex SMAD2_3*:SMAD4 map


Complex composition:

  1. SMAD4 map
  2. SMAD2_3* map




(SMAD2_3*:​SMAD4)|​active@Cytoplasm

Identifiers
NAME:SMAD2_3*:SMAD4

Maps_Modules
 EMT  map  / EMT_REGULATORS  map

References
PMID:11792802
-Unphosphorylated Smad proteins exist primarily as monomers
-Upon phosphorylation, R-Smads form homo-oligomers, which quickly convert to hetero-oligomers containing Smad4
PMID:11170475
Phosphorylated C-ter tail of R-Smads interacts specifically with the L3 loop of another Smad, which is sufficient to cause their oligomerization
PMID:9865696
Phosphorylation of Smad2 induces dissociation from SARA
with concomitant formation of Smad2/ Smad4 complexes
and nuclear translocation.
PMID:8893010
All mammalian R-Smads and Smad4 reside in the cytoplasm
Phosphorylated R-Smads quickly form complexes with Smad4 and possibly prior to nuclear translocation
PMID:9389648
Nuclear translocation of R-Smads is independent of Smad4
Whereas translocation of Smad4 after TGFB siglaing seems to require the presence of an activated R-Smad
e_re225( EMT  map ):

Confidence
REF=4 FUNC=5

SMAD2_3*:​SMAD4@Nucleus

Identifiers
NAME:SMAD2_3*:SMAD4

Maps_Modules
 EMT  map  / EMT_REGULATORS  map

References
PMID:11792802
-Unphosphorylated Smad proteins exist primarily as monomers
-Upon phosphorylation, R-Smads form homo-oligomers, which quickly convert to hetero-oligomers containing Smad4
PMID:11170475
Phosphorylated C-ter tail of R-Smads interacts specifically with the L3 loop of another Smad, which is sufficient to cause their oligomerization
PMID:9865696
Phosphorylation of Smad2 induces dissociation from SARA
with concomitant formation of Smad2/ Smad4 complexes
and nuclear translocation.
PMID:8893010
All mammalian R-Smads and Smad4 reside in the cytoplasm
Phosphorylated R-Smads quickly form complexes with Smad4 and possibly prior to nuclear translocation
PMID:9389648
Nuclear translocation of R-Smads is independent of Smad4
Whereas translocation of Smad4 after TGFB siglaing seems to require the presence of an activated R-SmadPMID:20731704 PMID:21317430 PMID:22406545
e_re225( EMT  map ):
Whereas translocation of Smad4 after TGFB siglaing seems to require the presence of an activated R-Smad
e_re1( EMT  map ):
PMID:20731704
PMID:21317430
In NMuMG cells treated with TGFB1 Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6–8 h.
Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation
PMID:22406545
TGFB can activate both SNAI1 and SNAI2 and thus promote EMT via both SMAD-dependent and -independent pathways
PMID:16617148
Negative feedback by SNAI1 itself
PMID:17671186
KLF8 directly bound to the promotor of Snail and repressed Snail expression
PMID:17563753
Snail promoter is regulated positively by NFkB_p65
PMID:16831886
PMID:18832382
HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression.
HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter.
Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1
HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression
e_re2( EMT  map ):
PMID:14623871
Activation of Slug (SNAI2) by two mechanisms:
-transcriptional activation of Slug by the CTNNB1and TCF/LEF complex
-activation of the ERK pathway.
When adherens junctions are established in dense cultures, ErbB1/2 and the ERK pathway become inactive, CTNNB1 is localized at adherens junctions, Slug expression is reduced, and E-cadherin transcription is induced.
Antibody-mediated disruption of adherens junctions led to nuclear CTNNB1 localization and enhanced beta-catenin signaling, induction of Slug and inhibition of E-cadherin expression.
PMID:17093497
PMID:12490555
Snail1 induces Snail2 transcription.
Snail is able to induce the expression of Slug and all other neural crest markers (Zic5, FoxD3, Twist and Ets1)
PMID:16510505
Snail2 activates the Snail2 promoter
PMID:21199805
Twist1 binds to an E-box on the proximate Snail2 promoter to induce its transcription.
PMID:17550342
Activation of KIT by binding to KITLG induces SNAI2 expression
e_re4( EMT  map ):
PMID:19208835
TCF8 (ZEB1) is up-regulated in endothelial cells during angiogenesis, acting as a negative regulator.
Snail1 controls Zeb1 expression at multiple levels and acts cooperatively with Twist in the ZEB1 gene transcription induction
e_re6( EMT  map ):
PMID:21883379
PMID:18297062
TWIST is a downstream target of HIF-1
Hypoxia or HIF-1 induces EMT through the direct activation of TWIST expression
PMID:19412634
Twist is a target of Snail1
PMID:22945800
Expression of Twist1 and Snail1 are mutually dependent
Knock-down of Snail1 downregulates Twist1 protein and mRNA
Knock- down of Twist1 interferes with TGFb-mediated induction of Snail1.
PMID:22006115
Alternatively, it has also been reported that Snail1 transcriptionally represses Twist1
e_re252( EMT  map ):
PMID:11013220
Cooperation and physical interaction of Smad2, Smad3, Smad4 with SP1 at the promoter of CDKN2B (p15INK4B) gene
This interaction provides a mechanism underlying the TGFB-induced growth arrest
Smads and SIP form a nucleoprotein complex on the p15INK4B promotor
Expression of p15INK4B induced by TGFB requires Smad2, Smad3 and Smad4
e_re1261( EMT  map ):
PMID:12718878
TGFB can activate ATF3 transcription via direct binding of Smad proteins to the ATF3 promoter.
Then Smad3, Smad4, and ATF3 Bind to the Id1 Promoter in Response to TGFB

Confidence
REF=5 FUNC=5


Modifications:
Participates in complexes:
In compartment: Cytoplasm
  1. (SMAD2_3*:​SMAD4)|​active@Cytoplasm map

In compartment: Nucleus

  1. SMAD2_3*:​SMAD4@Nucleus map

Participates in reactions:
As Reactant or Product:

  1. (SMAD2_3*:​SMAD4)|​active@Cytoplasm map map SMAD2_3*:​SMAD4@Nucleus map

  2. SMAD2_3*:​SMAD4@Nucleus map + ATF3@Nucleus map map ATF3:​SMAD2_3*:​SMAD4@Nucleus map
  3. (SMAD2_3*:​SMAD4)|​active@Cytoplasm map map SMAD2_3*:​SMAD4@Nucleus map
  4. SMAD4@Cytoplasm map + SMAD2_3*@Cytoplasm map map (SMAD2_3*:​SMAD4)|​active@Cytoplasm map
  5. ZEB1@Nucleus map + SMAD2_3*:​SMAD4@Nucleus map map SMAD2_3*:​SMAD4:​ZEB1@Nucleus map
  6. SMAD2_3*:​SMAD4@Nucleus map + SP1@Nucleus map map (SMAD2|​S467_pho|​S464_pho|​S465_pho:​SMAD3|​S422_pho|​S423_pho|​S425_pho:​SMAD4:​SP1)|​active@Nucleus map

As Catalyser:

  1. gSNAI1@Nucleus map map rSNAI1@Nucleus map

  2. gATF3@Nucleus map map rATF3@Nucleus map
  3. gSNAI2@Nucleus map map rSNAI2@Nucleus map
  4. gZEB1@Nucleus map map rZEB1@Nucleus map
  5. gZEB2@Nucleus map map rZEB2@Nucleus map
  6. gTWIST1@Nucleus map map rTWIST1@Nucleus map
  7. gTWIST2@Nucleus map map rTWIST2@Nucleus map

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