SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription

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Homo sapiens
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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).

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).

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).

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).

JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999).

Literature References
PubMed ID Title Journal Year
14657019 Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7

Koinuma, D, Shinozaki, M, Komuro, A, Goto, K, Saitoh, M, Hanyu, A, Ebina, M, Nukiwa, T, Miyazawa, K, Imamura, T, Miyazono, K

EMBO J 2003
18568018 TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal

Varelas, X, Sakuma, R, Samavarchi-Tehrani, P, Peerani, R, Rao, BM, Dembowy, J, Yaffe, MB, Zandstra, PW, Wrana, JL

Nat Cell Biol 2008
11274402 Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling

Kaji, H, Canaff, L, Lebrun, JJ, Goltzman, D, Hendy, GN

Proc Natl Acad Sci U S A 2001
11294908 Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner

Kurisaki, A, Kose, S, Yoneda, Y, Heldin, CH, Moustakas, A

Mol Biol Cell 2001
22275377 Impaired Transforming Growth Factor-? (TGF-?) Transcriptional Activity and Cell Proliferation Control of a Menin In-frame Deletion Mutant Associated with Multiple Endocrine Neoplasia Type 1 (MEN1)

Canaff, L, Vanbellinghen, JF, Kaji, H, Goltzman, D, Hendy, GN

J Biol Chem 2012
15150273 Menin is required for bone morphogenetic protein 2- and transforming growth factor beta-regulated osteoblastic differentiation through interaction with Smads and Runx2

Sowa, H, Kaji, H, Hendy, GN, Canaff, L, Komori, T, Sugimoto, T, Chihara, K

J Biol Chem 2004
10022869 Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta

Wong, C, Rougier-Chapman, EM, Frederick, JP, Datto, MB, Liberati, NT, Li, JM, Wang, XF

Mol Cell Biol 1999
12592392 An extended bipartite nuclear localization signal in Smad4 is required for its nuclear import and transcriptional activity

Xiao, Z, Latek, R, Lodish, HF

Oncogene 2003
10934479 The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation

Xu, L, Chen, YG, Massague, J

Nat Cell Biol 2000
19914168 Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways

Alarcon, C, Zaromytidou, AI, Xi, Q, Gao, S, Yu, J, Fujisawa, S, Barlas, A, Miller, AN, Manova-Todorova, K, Macias, MJ, Sapkota, G, Pan, D, Massague, J

Cell 2009
12150994 E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression

Chen, CR, Kang, Y, Siegel, PM, Massague, J

Cell 2002
11013220 Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta

Feng, XH, Lin, X, Derynck, R

EMBO J 2000
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