Pathway
Downregulation of SMAD2/3:SMAD4 transcriptional activity
Transcriptional activity of SMAD2/3:SMAD4 heterotrimer can be inhibited by formation of a complex with SKI or SKIL (SNO), where SKI or SKIL recruit NCOR and possibly other transcriptional repressors to SMAD-binding promoter elements. Higher levels of phosphorylated SMAD2 and SMAD3, however, may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001) through recruitment of SMURF2 or RNF111 i.e. Arkadia ubiquitin ligases to SKI/SKIL by SMAD2/3. Therefore,the ratio of SMAD2/3 and SKI/SKIL determines the outcome: inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL. SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex.
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SMAD4 can be monoubiquitinated by a nuclear ubiquitin ligase TRIM33 (Ecto, Ectodermin, Tif1-gamma). Monoubiquitination of SMAD4 disrupts SMAD2/3:SMAD4 heterotrimers and leads to SMAD4 translocation to the cytosol. In the cytosol, SMAD4 can be deubiquitinated by USP9X (FAM), reversing TRIM33-mediated negative regulation.
Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8 or CDK9 primes SMAD2/3:SMAD4 complex for ubiquitination by NEDD4L and SMURF ubiquitin ligases. NEDD4L ubiquitinates SMAD2/3 and targets SMAD2/3:SMAD4 heterotrimer for degradation. SMURF2 monoubiquitinates SMAD2/3, leading to disruption of SMAD2/3:SMAD4 complexes.
Transcriptional repressors TGIF1 and TGIF2 bind SMAD2/3:SMAD4 complexes and inhibit SMAD-mediated transcription by recruitment of histone deacetylase HDAC1 to SMAD-binding promoter elements.
PARP1 can attach poly ADP-ribosyl chains to SMAD3 and SMAD4 within SMAD2/3:SMAD4 heterotrimers. PARylated SMAD2/3:SMAD4 complexes are unable to bind SMAD-binding DNA elements (SBEs).
Phosphorylated SMAD2 and SMAD3 can be dephosphorylated by PPM1A protein phosphatase, leading to dissociation of SMAD2/3 complexes and translocation of unphosphorylated SMAD2/3 to the cytosol.
What the reference databases state
Statements
29 statements
29 statements · 1 reference database · Subject: Downregulation of SMAD2/3:SMAD4 transcriptional activity · Sources: Reactome
- ATP1B4 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- HDAC1 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- MAPK1 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- MAPK3 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- NCOR1 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- NCOR2 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- NEDD4L participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- PARP1 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- PPM1A participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- RNF111 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- RPS27A participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- SKI participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
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- SKIL participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- SMAD2 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- SMAD3 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- SMAD4 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- SMAD7 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- SMURF2 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- SNW1 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- TGIF1 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- TGIF2 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- TRIM33 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- UBA52 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- UBB participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- UBC participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- UBE2D1 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- UBE2D3 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- USP9X participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only
- WWTR1 participates in Downregulation of SMAD2/3:SMAD4 transcriptional activityProteinReactome R-HSA-2173795Inferred only