SMAD2/3:SMAD4转录活性下调
中文名称
通路描述
SMAD2/3:SMAD4异三聚体转录活性可通过与SKI或SKIL（SNO）形成复合物而被抑制，其中SKI或SKIL招募NCOR和可能的其他转录抑制因子到SMAD结合启动子元件上（Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999）。然而，磷酸化SMAD2和SMAD3水平较高时，可能通过招募SMURF2（Bonni et al. 2001）或RNF111（即Arkadia）（Levy et al. 2007）泛素连接酶到SMAD2/3，使SMAD2/3降解SKI/SKIL。因此，SMAD2/3与SKI/SKIL的比例决定了结果：抑制SMAD2/3:SMAD4介导的转录或降解SKI/SKIL。SKI和SKIL在各种癌症类型中过表达，其致癌作用与其抑制TGF-β受体复合物的信号传导能力有关。
SMAD4可由核泛素连接酶TRIM33单泛素化（Ecto, Ectodermin, Tif1-gamma）。SMAD4的单泛素化破坏了SMAD2/3:SMAD4异三聚体，导致SMAD4转位至细胞质。在细胞质中，SMAD4可由USP9X（FAM）去泛素化，逆转TRIM33介导的负调控（Dupont et al. 2009）。
CDK8或CDK9磷酸化SMAD2和SMAD3的 linker 区域，使SMAD2/3:SMAD4复合物对NEDD4L和SMURF泛素连接酶的泛素化进行准备。NEDD4L泛素化SMAD2/3，并靶向SMAD2/3:SMAD4异三聚体进行降解（Gao et al. 2009）。SMURF2单泛素化SMAD2/3，导致SMAD2/3:SMAD4复合物的破坏（Tang et al. 2011）。
转录抑制因子TGIF1和TGIF2结合SMAD2/3:SMAD4复合物，通过招募组蛋白去乙酰化酶HDAC1到SMAD结合启动子元件上抑制SMAD介导的转录（Wotton et al. 1999, Melhuish et al. 2001）。
PARP1可将多聚ADP-核糖链连接到SMAD3和SMAD4的SMAD2/3:SMAD4异三聚体内。PARylated SMAD2/3:SMAD4复合物无法结合SMAD结合DNA元件（SBEs）（Lonn et al. 2010）。
磷酸化SMAD2和SMAD3可由PPM1A蛋白磷酸酶去磷酸化，导致SMAD2/3复合物的解离和未磷酸化SMAD2/3转位至细胞质（Lin et al. 2006）。
SMAD4可由核泛素连接酶TRIM33单泛素化（Ecto, Ectodermin, Tif1-gamma）。SMAD4的单泛素化破坏了SMAD2/3:SMAD4异三聚体，导致SMAD4转位至细胞质。在细胞质中，SMAD4可由USP9X（FAM）去泛素化，逆转TRIM33介导的负调控（Dupont et al. 2009）。
CDK8或CDK9磷酸化SMAD2和SMAD3的 linker 区域，使SMAD2/3:SMAD4复合物对NEDD4L和SMURF泛素连接酶的泛素化进行准备。NEDD4L泛素化SMAD2/3，并靶向SMAD2/3:SMAD4异三聚体进行降解（Gao et al. 2009）。SMURF2单泛素化SMAD2/3，导致SMAD2/3:SMAD4复合物的破坏（Tang et al. 2011）。
转录抑制因子TGIF1和TGIF2结合SMAD2/3:SMAD4复合物，通过招募组蛋白去乙酰化酶HDAC1到SMAD结合启动子元件上抑制SMAD介导的转录（Wotton et al. 1999, Melhuish et al. 2001）。
PARP1可将多聚ADP-核糖链连接到SMAD3和SMAD4的SMAD2/3:SMAD4异三聚体内。PARylated SMAD2/3:SMAD4复合物无法结合SMAD结合DNA元件（SBEs）（Lonn et al. 2010）。
磷酸化SMAD2和SMAD3可由PPM1A蛋白磷酸酶去磷酸化，导致SMAD2/3复合物的解离和未磷酸化SMAD2/3转位至细胞质（Lin et al. 2006）。
英文描述
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 (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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
所含基因
29 个基因