Downregulation of SMAD2/3:SMAD4 transcriptional activity

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Homo sapiens
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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).
Literature References
PubMed ID Title Journal Year
10535941 SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling

Lodish, HF, Ng-Eaton, E, Sun, Y, Liu, X, Weinberg, RA

Proc Natl Acad Sci U S A 1999
11427533 TGIF2 interacts with histone deacetylase 1 and represses transcription

Melhuish, TA, Gallo, CM, Wotton, D

J Biol Chem 2001
11389444 TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation

Wrana, JL, Luo, K, Bonni, S, Wang, HR, Stroschein, SL, Causing, CG, Kavsak, P

Nat Cell Biol 2001
17591695 Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation

Episkopou, V, Levy, L, Harkin, S, Hill, CS, Das, D, Howell, M

Mol Cell Biol 2007
10199400 A Smad transcriptional corepressor

Massague, J, Lee, S, Lo, RS, Wotton, D

Cell 1999
19135894 FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination

Stinchfield, MJ, Montagner, M, Morsut, L, Piccolo, S, Inui, M, Moro, S, Mamidi, A, Newfeld, SJ, Soligo, S, Dupont, S, Argenton, F, Martello, G, Modena, N, Adorno, M, Zacchigna, L, Cordenonsi, M

Cell 2009
19917253 Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling

Massague, J, Chen, PY, Macias, MJ, Tempst, P, Goerner, N, Gao, S, Sapkota, G, Alarcon, C, Erdjument-Bromage, H, Rahman, S

Mol Cell 2009
21095583 PARP-1 attenuates Smad-mediated transcription

Dahl, M, Lönn, P, Moustakas, A, Hellman, U, van der Heide, LP, Heldin, CH

Mol Cell 2010
16751101 PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling

Wrighton, KH, Shi, Y, Liang, YY, Brunicardi, FC, Duan, X, Feng, XH, Chen, YG, Su, Y, Lin, X, Hu, M, Meng, A, Wang, J, Davis, CM, Long, J

Cell 2006
10549282 Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling

Sun, Y, Liu, X, Lodish, HF, Eaton, EN, Lane, WS, Weinberg, RA

Mol Cell 1999
10485843 The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling

Zhou, Q, Luo, K, Zhou, S, Martens, E, Stroschein, SL, Chen, D, Wang, W

Genes Dev 1999
10531062 Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein

Zhou, Q, Luo, K, Zhou, S, Stroschein, SL, Wang, W

Science 1999
22045334 Ablation of Smurf2 reveals an inhibition in TGF-? signalling through multiple mono-ubiquitination of Smad3

Zhang, YE, Coussens, NP, Tang, LY, Li, C, Tang, Y, Deng, CX, Yamashita, M, Cheng, SY, Wang, X

EMBO J 2011
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