Degradation of Ub-SMAD7 PathwayStep120 PathwayStep121 PathwayStep122 PathwayStep123 PathwayStep124 PathwayStep119 PathwayStep117 PathwayStep118 PathwayStep115 PathwayStep116 PathwayStep113 PathwayStep114 PathwayStep111 PathwayStep112 PathwayStep110 PathwayStep109 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription After phosphorylated SMAD2 and/or SMAD3 form a heterotrimer with SMAD4, SMAD2/3:SMAD4 complex translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003). In the nucleus, linker regions of SMAD2 and SMAD3 within SMAD2/3:SMAD4 complex can be phosphorylated by CDK8 associated with cyclin C (CDK8:CCNC) or CDK9 associated with cyclin T (CDK9:CCNT). CDK8/CDK9-mediated phosphorylation of SMAD2/3 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes it for ubiquitination and consequent degradation (Alarcon et al. 2009). <br><br>The transfer of SMAD2/3:SMAD4 complex to the nucleus can be assisted by other proteins, such as WWTR1. In human embryonic cells, WWTR1 (TAZ) binds SMAD2/3:SMAD4 heterotrimer and mediates TGF-beta-dependent nuclear accumulation of SMAD2/3:SMAD4. The complex of WWTR1 and SMAD2/3:SMAD4 binds promoters of SMAD7 and SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) genes and stimulates their transcription (Varelas et al. 2008). Stimulation of SMAD7 transcription by SMAD2/3:SMAD4 represents a negative feedback loop in TGF-beta receptor signaling. SMAD7 can be downregulated by RNF111 ubiquitin ligase (Arkadia), which binds and ubiquitinates SMAD7, targeting it for degradation (Koinuma et al. 2003). <br><br>SMAD2/3:SMAD4 heterotrimer also binds the complex of RBL1 (p107), E2F4/5 and TFDP1/2 (DP1/2). The resulting complex binds MYC promoter and inhibits MYC transcription. Inhibition of MYC transcription contributes to anti-proliferative effect of TGF-beta (Chen et al. 2002). SMAD2/3:SMAD4 heterotrimer also associates with transcription factor SP1. SMAD2/3:SMAD4:SP1 complex stimulates transcription of a CDK inhibitor CDKN2B (p15-INK4B), also contributing to the anti-proliferative effect of TGF-beta (Feng et al. 2000). <br><br>MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, forms a complex with SMAD2/3:SMAD4 heterotrimer, but transcriptional targets of SMAD2/3:SMAD4:MEN1 have not been elucidated (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012). <br><br>JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999). Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0045944 Pubmed10022869 Pubmed10934479 Pubmed11013220 Pubmed11274402 Pubmed11294908 Pubmed12150994 Pubmed12592392 Pubmed14657019 Pubmed15150273 Pubmed18568018 Pubmed19914168 Pubmed22275377 Reactome Database ID Release 432173796 Reactome, http://www.reactome.org ReactomeREACT_120734 Reviewed: Huang, Tao, 2012-05-14 RNF111 binds SMAD7 RNF111 ubiquitinates SMAD7 SMAD2/3:SMAD4 heterotrimer forms a complex with RBL1, E2F4/5 and DP1/2 MYC trancscription is negatively regulated by SMAD2/3:SMAD4:RBL1:E2F4/5:DP1/2 complex WWTR1:SMAD stimulates transcription of SERPINE1 while TGIF:SMAD inhibits it SMAD2/3:SMAD4 heterotrimer binds SP1 SMAD2/3:SMAD4:SP1 complex stimulates transcription of CDKN2B MEN1 binds SMAD2/3:SMAD4 heterotrimer SMAD2/3:SMAD4 complex positively regulates JUNB transcription WWTR1:SMAD translocates to the nucleus WWTR1:SMAD stimulates transcription of SMAD7 Phosphorylation of SMAD2 and SMAD3 linker regions by CDK8 or CDK9 WWTR1 binds SMAD2/3:SMAD4 heterotrimer Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4 The SMAD2/3:SMAD4 complex transfers to the nucleus