Identifiers
NAME:SMAD3:SMAD4
Maps_Modules
HMC:ACTIVATING_INVASION_AND_METASTASIS
EMT Senescence / EMT_REGULATORS
References
em_emtc_emtc_re233( EMT Senescence ):
PMID:11792802
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
em_emtc_emtc_re4( EMT Senescence ):
PMID:20731704
PMID:19208835
TCF8 (ZEB1) is up-regulated in endothelial cells during angiogenesis, acting as a negative regulator.
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
Snail1 controls Zeb1 expression at multiple levels and acts cooperatively with Twist in the ZEB1 gene transcription induction
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
em_emtc_emtc_re235( EMT Senescence ):
PMID:19597490
SMAD3 and SMAD4 interact and form a complex with SNAIL1
em_emtc_emtc_re1363( EMT Senescence ):
PMID:14976548
TGFB stimulates two kinetically coordinated waves of activation of HEY1.
Immediate-early activation of HEY1 by TGFB is mediated directly by Smad3/4 binding at two distinct sequences in the distal HEY1 promoter region and does not require Notch signalling.
The Smad-dependent, Notch-independent immediate-early activation is followed by a second wave of HEY1 activation.
This second wave is mediated by classical Notch-dependent signalling induced through indirect and delayed induction of Jag1 synthesis by TGFB
Identifiers
NAME:SMAD3:SMAD4
Maps_Modules
HMC:TUMOR_PROMOTING_INFLAMMATION
HMC:ACTIVATING_INVASION_AND_METASTASIS
Cancer Associated Fibroblasts / GROWTH_FACTORS_SIGNALING_PATHWAYS
References
CASCADE:TGFB
PMID:11013125 ; PMID:11376132
CTGF expression is induced by TGF- beta in fibroblasts via SMAD3 and SMAD4 pathway
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 translocatio
PMID:12702545, PMID:8515656
Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression.
PMID:23784029
Smad??7??is bound to??Smad??2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-??1 stimulation.
PMID:21098712; PMID:22652804; PMID:25374926
TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways (erk,jnk,p38)
Identifiers
NAME:SMAD3:SMAD4
Maps_Modules
HMC:TUMOR_PROMOTING_INFLAMMATION
Innate Immunity / IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS
References
MACROPHAGE
NATURAL_KILLER
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 translocatio
in_re471( Innate Immunity ):
PMID:12193690
Up-regulation of IL4RA by IL10 correlates with increased
IL4-dependent expression of arginase-1 (ARG1).
PMID:10925299, PMID:6357187
IL-13 induces de novo synthesis of arginase I mRNA and protein. Probably via STAT6.
PMID:23390297
MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23.
in_re485( Innate Immunity ):
PMID:11875494
HMOX1 (HO1) mediates the inhibitory effect of IL10
on LPS-induced NOS2 (INOS) expression.
PMID:6357187, PMID:8871614
IL13 downregulates INOS activity via ILRA1/STAT6 pathway.
PMID:16127449
PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR???HDAC3 complex fro promoters and
transrepresses NF-kB dependent expression NOS2, Ccl3, Ccl7, Cxcl10.
PMID:15644117, PMID:17260466
HMGB1 induces NO production probably via NFkB dependent upregulation of INOS expression.
PMID:17689680
STAT1 binds to INOS promoter and induces INOS expression and NO production downstream of IFNG in murine macrophages. Acetylation inhibits STAT1 binding to promotor.
PMID:11399519
STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG.
MIF inhitits expression of M1 markers such as NOS2 (INOS).
PMID;PMID:20194441
HIF1 upregulates expression of INOS.
+ SMAD4@Cytosol → SMAD3|pho:SMAD4@Cytosol
(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
+ SP1@Nucleus → SMAD3|S423_pho|S425_pho|hm2:SMAD4:SP1@Nucleus
+ SMAD4@INNATE_IMMUNE_CELL_Cytosol → SMAD3|pho:SMAD4@INNATE_IMMUNE_CELL_Cytosol
→ 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
→ 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