Ubiquitin-dependent degradation of the SMAD complex terminates TGF-beta signaling Degradation of SMAD2/3:SMAD4 complex Degradation of ubiquitinated SKI/SKIL PathwayStep139 PathwayStep137 PathwayStep138 PathwayStep131 PathwayStep132 PathwayStep130 PathwayStep135 PathwayStep136 PathwayStep133 PathwayStep134 PathwayStep126 PathwayStep127 PathwayStep128 PathwayStep129 PathwayStep143 PathwayStep142 PathwayStep141 PathwayStep140 PathwayStep146 PathwayStep145 PathwayStep144 SMURF2 binds SMAD3 phosphorylated in the linker region Dephosphorylated SMAD2/3 translocates to the cytosol PPM1A protein phosphatase binds phosphorylated SMAD2/3 PPM1A dephosphorylates nuclear SMAD2/3 PARP1 binds SMAD2/3:SMAD4 heterotrimer PARP1 ADP-ribosylates SMAD3 and SMAD4 SMURF2 monoubiquitinates SMAD3 TGIF recruits HDAC1 to SMAD2/3:SMAD4 heterotrimer USP9X (FAM) binds to ubiquitinated SMAD4 USP9X (FAM) deubiquitinates SMAD4 NEDD4L binds phosphorylated linker region of SMAD2/3 NEDD4L ubiquitinates SMAD2/3 Ubiquitination of SKI/SKIL by RNF111/SMURF2 TRIM33 (Ectodermin) binds SMAD heterotrimer in the nucleus TRIM33 monoubiquitinates SMAD4 Ubiquitinated SMAD4 translocates from the nucleus to the cytosol SMAD2/3 activation induces binding of RNF111/SMURF2 to SKI/SKIL Downregulation of SMAD2/3:SMAD4 transcriptional activity Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0000122 Pubmed10199400 Pubmed10485843 Pubmed10531062 Pubmed10535941 Pubmed10549282 Pubmed11389444 Pubmed11427533 Pubmed16751101 Pubmed17591695 Pubmed19135894 Pubmed19917253 Pubmed21095583 Pubmed22045334 Reactome Database ID Release 432173795 Reactome, http://www.reactome.org ReactomeREACT_121111 Reviewed: Huang, Tao, 2012-05-14 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 (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). 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 (Bonni et al. 2001) or RNF111 i.e. Arkadia (Levy et al. 2007) 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. <br>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 (Dupont et al. 2009).<br>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 (Gao et al. 2009). SMURF2 monoubiquitinates SMAD2/3, leading to disruption of SMAD2/3:SMAD4 complexes (Tang et al. 2011). <br>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 (Wotton et al. 1999, Melhuish et al. 2001).<br>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) (Lonn et al. 2010). <br>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 (Lin et al. 2006). SKI/SKIL binds SMAD complex, suppressing TGF-beta signaling