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

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

Nat Cell Biol 2008
14657019 Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7

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

EMBO J 2003
11274402 Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling

Kaji, H, Lebrun, JJ, Canaff, L, 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

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

Kaji, H, Vanbellinghen, JF, Canaff, L, 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

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

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

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

Lodish, HF, Latek, R, Xiao, Z

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

Massague, J, Xu, L, Chen, YG

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

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

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

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

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

Lin, X, Feng, XH, Derynck, R

EMBO J 2000
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